Effective Molarities for Intramolecular Reactions

Effective Molarities for Intramolecular Reactions

Effective Molarities for Intramolecular Reactions ANTHONY J . KIRBY University Chemical Laboratory, Cambridge, England 1 Introduction 184 2 The effic...

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Effective Molarities for Intramolecular Reactions ANTHONY J . KIRBY

University Chemical Laboratory, Cambridge, England 1 Introduction 184 2 The efficiency of intramolecular catalysis I85 3 Calculation of effective molarities 187 4 Effective molarity and mechanism 190 Classification of reactions 190 Nucleophilic vs. general acid-base catalysis 191 Intramolecular general acid catalysis in reactions of salicylic acid derivatives 196 Why are EM’S for general acid-base catalysed reactions so low? 198 EM and the nature of the transition state 200 The formation of small rings 205 5 Effects of substitution on the EM for ring-closure reactions 208 The Thorpelngold effect 208 Effects on the formation of larger rings 216 The relief of ground-state strain 2 17 Orbital steering 222 6 Tables of effective molarities 223 Notes on Tables A-H 224 I EFFECTIVE MOLARWIES FOR CYCLEATION REACTIONS 225 A Reactions of the carboxylic acidgroup 225 A. 1 Equilibrium data for anhydride formation 225, A.2 Intramolecular nucleophilic catalysis of ester hydrolysis 226, A.3 Intramolecular nucleophilic catalysis of amide hydrolysis 23 1, A.4 Lactone formation from w-halogenocarboxylates 234, A S Intramolecular nucleophilic catalysis of phosphate and phosphonate ester hydrolysis 235, A.6 Intramolecular nucleophilic catalysis of the hydrolysis of sulphonamides 238 B Reactions of the hydroxyl group 239 B.l Equilibrium constants for the lactonization of hydroxy acids 239, B.2 Acidcatalysed lactonization of hydroxy acids 24 1, B.3 Base-catalysed lactonization of hydroxy esters 245, B.4 Epoxide formation from chlorohydrins 246, B.5 Base-catalysed formation of cyclic ethers 247, B.6 Intramolecular cyclization of hydroxyalkyl phosphates 25 1 C Reactions of the surphydryl group 252 C.l Equilibrium constants for thiolactone formation from pthiolacids 252, C.2 Thiolactonization of pthiolacids, etc. 253 D Reactions of the amino-group 254 D.la Intramolecular attack by the dialkylamino-group on a neighbouring ester group 254, D. l b Intramolecular nucleophilic attack by imidazole and pyridine 255, D.2 Intramolecular attack by the NHR group 256, D.3 The cyclization of halogeno-amines, etc. 256, D.4 Intramolecular nucleophilic attack on phosphorus 259 183

ANTHONY J

184

KIRBY

I1 INTRAMOLECULAR GENERAL BASE CATALYSIS 259 E Catalysis by the ionized carboxylgroup 259 E. 1 Intramolecular general base catalysis of ester hydrolysis 259, E.2 Intramolecular general base catalysis of Schiffs base hydrolysis 262, E.3 Intramolecular general base catalysis of enolization 262 F Intramolecular general base catalysis by phenolate oxygen 264 F.1 Catalysis of ester hydrolysis 264, F.2 Catalysis of enolization 265 G Intramolecular general base catalysis by nitrogen 266 G. 1 Catalysis of ester hydrolysis 266, G.2 Intramolecular general base catalysis of enolization 269, G.3 Intramolecular general base catalysis of aminolysis by the amino-group 270 I11 INTRAMOLECULAR GENERAL ACID CATALYSIS 271 H.l Intramolecular general acid catalysis by the carboxyl group 271, H.2 Intramolecular general acid catalysis by the hydroxyl group 273 References 274

1

Introduction

The extraordinary efficiency of enzyme catalysis has stimulated a great deal of chemistry in recent years. Enzymes promote very fast reactions, often between functional groups which are normally exceedingly unreactive, under the mildest conditions of temperature and pH, by bringing the groups together under the special conditions of the enzyme-substrate complex. These conditions may be special in various ways, but it is clear that a major part of the very large rate enhancements involved is due simply to the way the functional groups concerned are brought together. Consequently it is of particular interest to study the same reactions between the same groups in systems simple enough to understand in detail. The first step towards unravelling the mechanism of an enzyme-catalysed reaction is to be able to specify the mechanisms available for the reaction concerned. Many of these reactions are not observed at all when the relevant groups are allowed to come together in bimolecular processes in aqueous solution. For mechanistic work involving intermolecular reactions, therefore, it is necessary to use activated substrates. Much of what we know about the relevant reactions of esters, for example, comes from studies using aryl esters like p-nitrophenyl acetate, or acyl-activated compounds like ethyl trifluoroacetate (Bruice and Benkovic, 1966; Jencks, 1969; Bender, 1971). An attractive alternative is to study intramolecular reactions. These are generally faster than the corresponding intermolecular processes, and are frequently so much faster that it is possible to observe those types of reaction involved in enzyme catalysis. Thus groups like carboxyl and imidazole are involved at the active sites of many enzymes hydrolysing aliphatic esters and amides. Bimolecular reactions in water between acetic acid or imidazole and substrates such as ethyl acetate and simple amides are frequently too slow to

185

EFFECTIVE M O L A R l T l E S

detect even under vigorous conditions. But when the catalytic and substrate groups are brought together in the same molecule such otherwise unreactive compounds may be hydrolysed under quite mild conditions. Mechanistic studies of intramolecular reactions of this sort have therefore played an important part in elucidating the chemistry of the groups involved in enzyme catalysis and in defining the mechanisms available for particular reactions. Though such purely mechanistic work continues, recent studies of intramolecular catalysis have been concerned more and more with the factors responsible for the high efficiency of enzyme catalysis. It is now possible to write quite detailed-and quite plausible-mechanisms for certain enzyme reactions (Fersht, 1977); it is not so easy to account for their very high rates. Since some simple intramolecular reactions are very fast, in some cases going at rates comparable with similar enzyme reactions (Fife, 1975), it seems reasonable to suppose that an understanding of how efficiency depends on structure in intramolecular catalysis will shed some light on the related problems of enzyme catalysis. If reactivity does depend crucially on the way functional groups are brought together it should be possible to identify the factors involved by bringing groups together in different ways on the same molecule and observing the effect on reactivity. This problem has been reviewed (Page, 1973; Jencks, 1975), and the general conclusion emerging from a great deal of work is that it is possible to account for the efficiency of enzyme catalysis in terms of known concepts (Fersht, 1977; Fersht and Kirby, 1980). 2

The efficiency of intramolecular catalysis

If we are to examine systematically how catalytic efficiency depends on structure we need to define a convenient measure of efficiency. One measure commonly used is the magnitude of the rate acceleration observed for the reaction under consideration. For example, the rate of hydrolysis of the anion of aspirin [ 11, which is known to involve catalysis by the carboxylate group (Fersht and Kirby, 1967), is about 50 times faster than that of phenyl acetate under the same conditions at pH 7. This figure is easily defined because both reactions are pH-independent over a considerable range. The same comparison for an acetal such a 2-methoxymethoxybenzoic acid [21 on the other hand is less straightforward. Hydrolysis is catalysed by the neighbouring COOH group in a reaction which shows a small pH-independent region near pH 2 OCOCH,

OCH,OCH, COOH

[ll

[21

186

ANTHONY J. KIRBY

(Capon et al., 1969). There is no such region for the hydrolysis of methoxymethoxybenzene, which is specific acid catalysed; the relative rates depend on the pH taken. In a case like this the practice is therefore to quote the maximum rate enhancement, The efficiency of catalysis defined in this way has some uses, particularly when absolute rates of reaction are important. The values do not, however, allow the sensible comparison of efficiency in different reactions because like is not being compared with like. The hydrolysis of aspirin involves intramolecular general base catalysis of the attack of water by the COO- group 131, whereas that of phenyl acetate involves water alone [41 (Kirby, 1972); so the ratio of hydrolysis rates contains, as a hidden factor, the relative efficiencies as general bases in this particular reaction of water and the carboxylate group of aspirin. The similar comparison for 121 is between COOH as a general acid, in a reaction where proton transfer and C-0 bond-breaking are concerted, and a specific acid catalysed reaction where the proton transfer is complete in the rate determining step; so a quite different hidden factor is built in to the simple rate ratio in this case. The solution to this problem is to compare the rate constant for the intramolecular reaction with that for the corresponding intermolecular process. In the case of aspirin hydrolysis [31 this would be general base catalysis of the hydrolysis 151 of aspirin by an external carboxylate group, RCOO-, of the same basicity as the carboxylate group of aspirin. The necessary data are

H,O:

I

/

H OPh

151

available. The first order rate constant (k,) for the hydrolysis of aspirin at 39' is 1.1 x s-l (Fersht and Kirby, 1967b), while that for the same reaction catalysed by acetate ion (k2)is 1.27 x dm3 mol-' s-' under the same

E F F ECTl V E M 0LA R I TI E S

187

conditions. The ratio k,/k, = 8.7 and has the dimensions of molarity. This figure underestimates the true effective molarity because acetate (pK, 4.76) is more basic than the carboxylate group of aspirin (3.69). The correction requires a knowledge of the linear free energy relationship between the basicity and reactivity of the general base. The Brransted /3 has been measured for this reaction, and is 0.30 (Fersht and Kirby, 1967) so an appropriate value of k, (8.4 x lo-’ dm3 mol-I s-l) can be calculated for the reaction with a carboxylate group of pK, = 3.69, and the correct effective molarity calculated as 13 M. The effective molarity (EM) is formally the concentration of the catalytic group (RCOO-in [51) required to make the intermolecular reaction go at the observed rate of the intramolecular process. In practice many measured EM’S represent physically unattainable concentrations, and the formal definition is probably relevant only in reactions (which will generally involve very large cyclic transition states) where the formation of the ring or cyclic transition state per se is enthalpically neutral, or in diffusion-controlled processes. For the formation of small and medium-sized rings and cyclic transition states the EM as defined above contains, and may indeed be dominated by, the enthalpy of formation of the cyclic form. This topic has been discussed briefly by Illuminati ef al. (1977) and will be treated at greater length in a future volume in this series. The measurement of accurate EM’S, as defined above, clearly has very stringent requirements. First, the mechanisms of both intermolecular and intramolecular reactions must be known and have been shown to be the same. Then acceptable rate measurements must be carried out under the same conditions for both reactions. Generally it is not possible to measure the rates of both the intermolecular reaction and the intramolecular process (thus catalysed by the same group) under the same conditions; measurements on the intermolecular reaction catalysed by a series of catalytic groups are necessary to define the EM accurately. Such stringent conditions are clearly not likely to be fulfilled by chance, and in fact data suitable for the accurate measurement of effective concentrations are available only for a handful of reactions. On the other hand, the range of EM’S known is very large (from zero to 1OI6 M) and, certain specialized uses apart, very accurate figures are not essential. 3

Calculation of effective molarities

In most cases the EM’S quoted in the tables in Section 6 are based on accurate measurements of k,,the rate constant for the intramolecular reaction (which is quoted for all the EM’S calculated here), and the rate constant for the closest equivalent intermolecular reaction under conditions which are as similar as

ANTHONY J. K I R B Y

188

possible. Except where otherwise indicated, the data are for reactions followed in aqueous solution. Comparison of rate constants at widely differing temperatures is only attempted when the enthalpy of activation is known for one or both reactions. The pK,-values quoted for nucleophilic, basic or acidic groups are generally those measured in the course of the work cited, but values have been estimated in a few instances or taken from tables. A small error in pK, affects the calculated EM relatively little in most cases. In a few, but important, cases, EM’S have been calculated not from rate constants but from product ratios. Where the effective molarity is low, competition between intramolecular and intermolecular reactions of the same compound may be observed, as in Freundlich’s early work on the cyclization of w-bromoalkylamines (1) described by Salomon (1936). The interH

H molecular reaction can be minimized by working at very low concentrations, but where both products are observed their ratio allows the calculation of the ratio of the rate constants for the intramolecular and the corresponding intermolecular reaction. This ratio was defined as the cyclization constant, C, by Stoll and Rouve (1934) and is identical to the EM as long as the bimolecular reaction is the most suitable model available for the intramolecular process. This will generally be the case except where data have been collected specifically for the estimation of EM’S. Thus Galli and Mandolini (1977) found that the alkylation of 8-bromooctanoate -by n-octyl bromide was 2.4 times faster than the intermolecular reaction with a second molecule of cubromoalkanoate, probably as a result of electrostatic repulsion. In this case a careful investigation of a large number of similar reactions under the same conditions produced a better intermolecular comparison. More usually such desirable data are not available, and for the purposes of this review the EM calculated from the product ratio in a reaction of this sort is considered acceptable (and rated if the measurements were done accurately enough). A second situation where EM’S can be calculated from product ratios, which again is applicable only for reactions with low EM, is exemplified by the cyclization of 3-chloropropanol (Richardson et al., 1971). The measured rates of cyclization of a series of cuchloroakanols in alkali show (Table B.5) that the formation of the four-membered ring is substantially less efficient than that of other small rings. A careful product analysis of the cyclization of 3chloropropanol in 40% methanol-water at a range of temperatures showed a

EFFECTIVE M 0 LAR IT1 ES

LOH

40% MeOH,

H,O, NaOH

fl

+

qH OMe

C1

50%

14%

189 +

&OH

(2)

OH 28%

constant product distribution, as indicated in (2). The relative rates of the reaction of the substrate with the neighbouring 0-group and with methoxide are thus 50 : 14. The concentration of MeOH in 40% aqueous methanol is 9.89 M, and the pK,-values of methanol and water are close enough that a correction for this factor is not necessary. Thus k,ntm/kwewis 2.77 M, and the EM (given in Table B.5 as 4 M, category p) is obtained by correcting this figure for the (small) difference in pK, between methanol and 3-chloropropanol. This analysis begs one question, which is essentially insoluble and which applies to many of the calculations described in the tables. Methoxide ion is clearly not a perfect model for neighbouring (CH,),CH,O-; but what is? Illuminati et al. (1977) solve the problem satisfactorily for reactions in which large rings are formed by measuring rates of reaction of a large number of possible intermolecular models (Galli and Mandolini, 1977), finally choosing a preferred reaction for comparison on the basis of all the available information. But the situation is different for reactions in which smaller rings are formed. For example, good data are available for the cyclization of chlorohydrins to epoxides (Table B.4). If we wish to compare EM’S in the series [6al, [6bl, [6cl

[6bl

the appropriate nucleophiles for comparison might be thought to be ethoxide, isopropoxide and t-butoxide, with progressively increasing steric hindrance. But it is clear that steric effects in intramolecular reactions, especially the formation of small rings, are much smaller than in the corresponding bimolecular processes. In fact reactivity increases sharply with increasing substitution in the series under discussion as a result of the well-known (though not well-understood) Thorpe-Ingold effect. In this case we do not have a wide choice of data for intermolecular reactions for comparison and so have used the same model reaction as has been used for the formation of the oxetane. This at least puts the two reactions on the same scale and ensures that we do not ooerestimate the Thorpe-Ingold effect. The tables at the end of this chapter contain nearly 400 EM’S which are considered accurate enough to be useful. In each case the intermolecular reaction used for comparison and the conditions used for the measurements

ANTHONY J K I R B Y

190

are specified, and any extrapolations used are described. Each figure is rated a, y for accuracy. Values rated a refer to EM’S calculated from measurements made for both intermolecular and intramolecular reactions under the same conditions, or involving only a short extrapolation known to be reliable. EM’S classified as 3/ (the majority) involve a substantial extrapolation (data at different temperatures, in different solvents etc.), while y indicates that the extrapolations involved are less reliable. Estimated errors are up to 10% for a figures, which are in many cases accurate to the significant figures given, a factor of two for category /3, and an order of magnitude for category y. These are generally generous error limits. The main tables are designated by a letter and a number (a full list is given in the Contents at the beginning of this chapter). Tables in the text, which mostly contain effective molarities taken from the main tables, are designated by a number only. Every individual reaction is identified by a reference letter and two numbers. Thus B.6.3 refers to the base-catalysed cyclization of cyclohexyl 2-hydroxyethyl phosphate which is the third entry in Table B.6. The EM for this reaction is given in Table 10 in the discussion of the effects of alkyl substitution on ring-closure, and the reference number quoted there. Full details of the calculation of the EM, the rate constant on which it is based, the conditions used and the authors concerned can then be found by consulting Table B.6.

/3 or

4

Effective molarity and mechanism

The data summarized in the tables are the source of most of our current ideas about the efficiency of ring-closure reactions (Eliel, 1962; Capon and McManus, 1976). We know, for example, that the ease of ring-formation generally depends on the size of the ring being formed, according to the series 3 > 4 < 5 > 6 > 7, etc. Large effects of this sort are readily apparent from simple rate comparisons which within a series of related compounds give ratios not very different from those obtained by comparing effective molarities. A more likely source of new insights is the comparison of EM’S for different reaction types, because most of the data have not previously been available in this form. So most of the discussion below concerns comparisons of this sort. CLASSIFICATION OF REACTIONS

Capon (1964; Capon and McManus, 1976) introduced a simple classification for reactions involving neighbouring group participation, in which G-n indicates participation by a nucleophilic group G in an n-membered cyclic transition state. For present purposes an extension of this symbolism is necessary in order that the abbreviations indicate the electrophilic centre also.

EFFECTIVE M O L A R l T l E S

191

Only a relatively small number of electrophilic centres are involved in the great majority of the reactions listed in Section I of the tables, and to avoid confusion they are given single letter abbreviations. For example, A, M and E indicate carboxylic acid, amide and ester groups respectively. (The full list is given at the beginning of the tables.) Finally the suffix x or n specifies exocyclic or endocyclic displacement of the leaving group. For displacements at tetrahedral carbon the terminology is similar to that used by Baldwin (1976), but for reactions at trigonal carbon his ex0 and endo refer to the initial addition step. For displacements at carbonyl and especially phosphorus centres the EM can depend significantly on whether the leaving group is endo- or exocyclic. The classification is illustrated in the examples given in Table 1, and in the tables of EM’S. The extension to general acid-base catalysed reactions presents some complications. Here three functional groups may be involved simultaneously in the transition state, and the third group may or may not be part of the same molecule as. the other two. When it is not, this is indicated by enclosing the relevant group descriptor in parentheses. The size of the transition state is also represented differently for proton-transfer processes. The X...Y distance in X.. H.. Y is commonly about If times that in X... Y, and, following Bell (see various references under his name), the size of cyclic transition states containing H is designated (n + i),where n is the number of heavy atoms (see last four examples in Table 1). This has the added advantage that the classification defines the type of mechanism also.

. .

NUCLEOPHILIC V S . GENERAL ACID-BASE CATALYSIS

The most striking result is the contrast between the absolute magnitudes of EM for the nucleophilic reactions in Tables A-D, and those for general acid-base catalysis in Tables E-H. For the ring-closure reactions EM’S range up to 1OI6 M, with values of 104-108 M common for the formation of five-membered rings from conformationally flexible systems, and higher values are readily attained by simple structural variation. The highest EM for general base catalysis (Tables E-G), on the other hand, is 80 M, and the great majority are less than 10 M. In the case of acyl salicylates it is possible to make a direct comparison of EM’S for nucleophilic and general base catalysis in the same system. For the nucleophilic reaction (COO--E-6n) 171 the EM can be calculated as 2.6 x lo7 M (compound A.2.35). By contrast the EM for the general base catalysed hydrolysis (COO-(HO)E--7fn) IS1 is 13 M. Both the absolute magnitudes and the effects on EM of structural variation are strikingly smaller for general base catalysed reactions. Thus gem-dialkyl substitution can have large effects on the rates of ring-closure reactions (see Table 8), but it appears to have little effect on the efficiency of general base catalysis. For example, intramolecular nucleophilic catalysis of ester hydrolysis is not

192

ANTHONY J. KIRBY

TABLE1 Examples of the symbolism used in the classification of reactions

COO--E-Sx

COOH-M-SX

n -n

HO

CO,H

O d = O

-d

HO-A-SX

0--C-3~

0

0

COO--P3-6n

COO-(HO)E--74n

OR COO--H-qx

N-HN(E)-+

OH-O=C(N)-qn

EFFECTIVE M O L A R l T l E S

HO,C

193

0

A.2.35 EM = 2.6 x 107 M

0

E.1.6 EM=13M

(71 [Sl observed for derivatives of malonic acid because this mechanism would involve a four-membered cyclic anhydride. Consequently the general base catalysis reaction can be observed in this system (Kirby and Lloyd, 1976b). For a comparison with a nucleophilic reaction of a similar compound we can use the hydrolysis of the sulphonamides A.6.1 and A.6.2.' This reaction 191 is 40 times faster for the gern-dimethyl compound (the effect is still larger for the formation of four-membered rings containing only first row elements: see Table 8). For the malonate reaction (E. 1.1 and 2) [ 101 the gern-dimethyl compound reacts only half as efficiently.

A.6.1,2 R=H R=Me

[91 E M = 4 x 106M E M = 8 x lO'M

E.1.1,2 [ 101 EM=25M EM=11M

A more extensive comparison is given in Table 2, where a much larger range of effective molarities is observed as a result of alkyl substitution in a rigid system. For the most reactive maleamic acids the relief of ground state strain is an important driving force for cyclization, as it appears to be also for the formation of small rings accelerated by gem-dialkyl substitution (see Section 5; p. 208). The changes in bond angle caused by the changing pattern of alkyl substitution are of the same order of magnitude for the maleamic acids and the malonic esters listed in Table 2; on the other hand, the resulting changes in It is known that four-membered rings containing phosphorus or sulphur are formed more readily than those containing only first-row elements, and the EM'S calculated for compounds A.6.1 and 2 allow a quantitative estimate of the importance of the effect. In this series the four-membered ring is formed almost as efficiently as the five [the EM for the hydrolysis of HO,C(CH,), S0,NMePh (A.6.3) is 2 x 10' MI

ANTHONY J. KIRBY

194

TABLE2 The contrasting effects of structural variation on EM for nucleophilic vs. general base catalysis by the carboxyl group System

Angle(48)

EM/M

118.4O

60

1100

25

106.2O

11

121.0, 121.7O

3 x 1013

126.8, 131.7O

6 x loxo

132.1, 133.4O

8 x lo3

General base catalysis

E.l.lb

70zAr H,C a ‘COT

E. 1.4b

C0,Ar P C O , Nucleophilic catalysis

A.3.17c

A*3.13

A.3.2ob

R

CONHMe

R

CO,H

Y

CONHMe

CO,H

CONHMe

CO,H Data taken from Kirby and Lloyd, 1976b, and Tables A.3 and E.l Angles are those for the diacid EM for R = Me, angles for R = isopropyl. EM is not much affected by this change in substitution

EFFECTIVE MOLARlTlES

195

effective molarity cover a range of nearly 1O'O for the hydrolysis of the maleamic acids which involves nucleophilic catalysis (Kirby and Lancaster, 1972), but change by less than one order of magnitude for the intramolecular general base catalysed hydrolysis of the malonate esters. These differences in absolute magnitude are large enough and sufficiently clear cut to make a useful criterion of mechanism. It is not always a simple matter to distinguish nucleophilic from general species catalysis. For general base catalysis consistent results from a series of four or five tests are conclusive (Kirby, 1979); for general acid catalysis the simplest test, the solvent deuterium isotope effect, is often inconclusive (Fersht and Kirby, 1971). The magnitude of the effective molarity, which is based on a single comparison of rate constants, is generally quite unambiguous. If the EM is greater than 80 M the mechanism is nucleophilic.' If it is less than 80 M the mechanism is almost certainly general acid or general base catalysis. These generalizations hold for reactions involving the formation of unstrained rings (specifically, for systems where there is no more strain in the cyclic product than in the ground state). They should not therefore be applied to reactions in which small (three- or four-membered) or large (sevenmembered or more) rings are formed. For the great majority of reactions of interest, however, in which five- or six-membered rings would be formed by the nucleophilic mechanism, the rule holds. For these classes there are just three exceptions in the Tables (neglecting the group of six compoundsZdiscussed specifically in the next section). These are shown in (3) and (4).

- o=c)+Br(3)

-3 Br

fi OQ

HN

N'O-

EM = 14.5 M

H N i o + x -

D.1.14 (X = SPr') D.l.10 (X= OPh)

(4)

EM=53M EM=13M

All three cases involve the formation of six-membered rings, as would be expected, since the formation of five-membered rings is generally much more efficient in conformationally flexible systems. The imidazole reactions present no real problem since the reference reaction used in each case was the attack of *With the important exception of acetals (and possibly certain other derivatives) of salicylic acid (compounds H.l.6-11; see the following section), which are hydrolysed with intramolecular general acid catalysis by the carboxyl group, with EM'S of the order of lo4 M

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A N T H O N Y J. KIRBY

imidazole on an acetyl derivative, and propionate and higher esters are generally less reactive than acetates by factors of at least two (Kirby, 1972). So the quoted error (a factor of two) is already biased towards a higher EM, which brings these reactions into line. The formation of Gvalerolactone from the 6-bromocarboxylate (A.4.5) appears to be a genuine exception. The formation of a six-membered ring in a reaction in which the new ring-bond is only partially formed in the transition state is expected to have a particularly low EM (see Section 4; p 200) and so it does. INTRAMOLECULAR GENERAL SALICYLIC A C I D DERIVATIVES

ACID

CATALYSIS

IN

REACTIONS

OF

Relatively few data are available (Table H) for reactions involving intramolecular general acid catalysis, but in most cases the EM’S fall in the same range as those for general base catalysis (Tables E-G). This is expected if EM is a characteristic transition-state property, because a general acid catalysed reaction is always the microscopic reverse of a general base catalysed process although in no case has the EM been measured in as shown in equation (9, both directions.

H.2.1

Reactions H. 1.6-1 1 therefore stand out as an important class of exceptions. The hydrolysis of these acetals of salicylic acid (e.g. [ 111) is catalysed by the neighbouring carboxyl group in a reaction which is certainly kinetically, and probably also mechanistically, general acid catalysis (Craze and Kirby, 1974), yet the effective molarities observed are far greater than any others measured for intramolecular general acid-base catalysis, and fall in the range characteristic of nucleophilic reactions. The nucleophilic mechanism has been ruled out for these reactions (it would require either an endocyclic displacement in a six-membered ring, or the formation of an intermediate known not to be reactive enough to support the reaction). It is therefore of the greatest interest to identify the factors which make this particular system so efficient’. Highly-efficient general acid catalysis of acetal hydrolysis is involved in the reactions of glycosidase enzymes such as lysozyme (Dunn and Bruice, 1973)

E F F ECTlV E M 0 LA R ITI E S

197

It is clear that the high efficiency is a property of the salicylate system and is not limited to acetal hydrolysis. Similar highly efficient catalysis is observed also in the hydrolysis of salicyl phosphate [12l,and a similar mechanism appears to be involved (Bromilow and Kirby, 1972). The essential structural

07p @?

ph*

0 H. 1.7, EM = 2.9 x lo4 M

0 Salicyl phosphate (EM not known)

[111

[121

feature can be further defined as the conjugation between the carboxyl and leaving groups by the results summarized in [131-[151. The EM for the cOMe

q\

PMe

OMe

H

H 0 0

[131 EM = lO‘M

0 [141 EM = 2 x lo4 M

0 [151 EM

<1M

hydrolysis of methoxymethyl benzoic acid [131 is not known, since the intermolecular reaction is not detectable in t h i s case. We therefore assume a value similar to the other salicylic acid acetals. The tetrahydro-derivative [ 141 is actually more reactive still, but the related compound [ 151,which has similar acetal, catalytic and leaving groups and differs only slightly in geometry, shows only very weak catalysis, if any (Kirby and Osborne, unpublished). Thus explanations which depend on the favourable (59ring-size can be ruled out, and we must look to a special property of the salicylate and related systems. It seems likely that this property is, or is related to, the strong hydrogen-bond formed in the salicylate anion. In Section 4 (p. 202) we shall consider the relationship between EM’s derived from rate constants and the EM’s for the corresponding equilibrium processes. Reactions with high “thermodynamic” EM’s generally have high kinetic EM’s also, depending upon the position of the transition state along the reaction co-ordinate. For almost all the reactions in Tables E-H no ring is being formed, so that the factors responsible for high EM’s in ring-closure reactions do not apply and high

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A N T H O N Y J. KIRBY

“thermodynamic” EM’S are not to be expected. The hydrolysis of a salicylate derivative (6), on the other hand, has one clear advantage over the corresponding intermolecular process (7) in the formation of a product with a strong intramolecular hydrogen-bond in water.

0

0

0

The “thermodynamic” EM for the hydrolysis of the salicylate derivative is therefore favoured by a factor presumably similar to that which favours the hydrogen-bonded form of the salicylate anion. In terms of the dissociation constant of the phenol group, which is some 3 pK units less acidic than expected for a phenol with an ortho-carboxylate group (Eberson, 1969), a factor of lo3,which is of the right order of magnitude to explain the observed effect, could be involved. This explanation is of particular interest, because it is practically certain that general acids and bases in the active sites of enzymes can form strong hydrogen bonds to suitably placed donors or acceptors on the protein. So the very low EM’s normally observed for general acid-base catalysed reactions in simple systems in water may well underestimate the EM’s available in enzyme active sites. Consequently the abnormal values seen with salicylate derivatives (which are clearly not ideal models for enzyme reactions since the leaving group is actually conjugated with the general acid) may actually be a better guide to the potential efficiency of general acid-base catalysis in enzyme reactions. W H Y A R E EM’S F O R G E N E R A L A C I D - B A S E C A T A L Y S E D R E A C T I O N S S O LOW?

A question of more general importance than why the EM’S for one small group of general acid catalysed reactions are exceptionally high, is why the EM’S for

EFFECTIVE MOLARlTlES

199

these reactions should otherwise be so low. We have already touched on one key factor, the fact the intramolecular nucleophilic reactions involve ring formation, so that the special factors favouring ring-closure affect the relative rates of similar intermolecular and intramolecular processes. We now consider these factors in a little more detail. Page and Jencks (1971; Page, 1973) have estimated the losses of translational and rotational entropy expected for the formation of the transition state for a typical bimolecular reaction as being of the order of 40-50 e.u. The size of this factor for a given reaction depends on the residual entropy of the transition state which is associated with a variable number of low frequency vibrations. The greater this residual entropy, that is to say, the looser the transition state, the greater and thus more favourable is the entropy of activation for the bimolecular process, and thus the smaller is the possible advantage of the intramolecular process. By way of example, compare the transition state [161 for a typical general base catalysed reaction (E.1.6) with that for the corresponding reaction involving a nucleophilic mechanism [171 (A.2.35). We have already seen that the EM’S for these mechanisms are 13 M and 2.6 x lo7M, respectively. In the

do? di )/o\H

0-

0“ [161

[171

transition state for the nucleophilic mechanism [ 171 only one sigma bond is being broken, and the six-membered ring is almost fully formed (the rate determining step is expected to be breakdown of the tetrahedral intermediate in a case like this). It is clear that the transition state for the general base catalysed reaction is altogether looser, with no less than four covalent bonds being made and broken simultaneously, three of them u-bonds and two of them involving bonds to hydrogen. This is a feature of every general acid-base catalysed reaction and a significant one since partial bonds to hydrogen are expected to involve particularly low-frequency vibrations (Bell et al., 1974). The advantage of the intramolecular reaction, which is primarily entropic, is thus much reduced for the general base catalysis mechanism because the transition state is so much looser. If this explanation is correct, the looseness of the proton-transfer part of the mechanism is evidently crucial, both because it is part of every general acid-base catalysed reaction, and more specifically because EM’S for reactions

200

ANTHONY J. K I R B Y

in which no other o-bonds are being broken (an example would be general base catalysed enolization, as in [181), though relatively high for general base catalysed reactions, are not substantially greater than those for general base catalysis of hydrolysis.

0

E.3.18 EM = 56 M I181

EM

A N D THE NATURE OF THE TRANSITION STATE

We have seen that the absolute magnitude of the EM may allow the assignment of a reaction to its broad mechanistic class (nucleophilic or general acid-base catalysis) because the tighter transition states associated with nucleophilic reactions give rise to much higher values. There is some evidence that this general correlation holds also within a series of nucleophilic reactions. Table 3 shows data for three cyclization reactions of carboxylic acid derivatives. In reaction A. 1.1 bond formation is complete. In the transition state for reaction A.2.1 the new ring-bond is more or less fully formed because the breakdown of the tetrahedral intermediate is rate determining, while reaction A.4.4 is an “intramolecular SN2 reaction” with the new bond only partially formed in the transition state. The EM’S for these reactions thus refer to progressively looser states, and it is consistent with the general correlation noted above that the observed value of the EM decreases in the same sequence. Reaction B.5.4, which might be expected to have a transition state similar to that of reaction A.4.4, in fact has a higher EM, but since nucleophile, leaving group and geometry have all changed it is difficult to assess the significance of this. Now the coresponding “SN2” reaction shows a larger EM than attack on an ester group (reaction B.3.1; five-membered ring formation). The difference between this system and reactions A. 1 and A.2 is that now theformation of the tetrahedral intermediate is rate determining (&oxide is a poorer leaving group than phenoxide) so that the new ring-bond is only partially formed in the transition states of both reactions. For the formation of the six-membered ring the EM’S are equal for the two cyclizations. Reaction B.3.2 is a case where both nucleophile and leaving group are aryloxide anions, and so the breakdown and formation of the tetrahedral intermediate should be close to balance. Compared with the “intramolecular SN2” reaction B.5.8, the EM is now equal

201

EFFECTIVE M O L A R l T l E S

TABLE3. Correlation between EM and the tightness of the transition state for the formation of five- and six-membered rings ~

_

_

Compound

A.l.l

_

_

_

_

(Transition) state

Succinic acid

EM-SIM

EMdM

1.9 x 10'

-

PhO,C(CH,),CO;A.2.1 A.2.21

n=2 n=3

5.1 x l(r 220

Br(CHJ,CO, A.4.4 A.4.5

n=3 n=4

B.3.1 B.3.5

n=3 n=4

1.6 x 103 14.5

PhO,C(CH,),O5 x 103 280

Cl(CH,),OB.5.4 B.5.9.

n=4 n=5

B.3.2 B.3.6

n=l n=2

6 x lo4

280

2.5 x 10'

\ B.5.8 B.5.10

n=2 n=3

5 x 104

0 1.3 x 10' 6.6 x lo3

(five-membered ring) or slightly larger (B.5.10; six-membered ring), as expected if the transition state is somewhat tighter for reaction B.3.6. It is interesting to attempt to extend this type of analysis in the direction of a more quantitative assessment of the degree of bond-making or breaking in the

2 02

A N T H O N Y J. KIRBY

transition state. We may distinguish two extreme cases. For the “infinitely loose” transition state where bond reorganization has not started (an example would be a diffusion-controlled reaction in the thermodynamically favoured direction), very low effective molarities are to be expected, presumably in the region of 55/n (where n is the number of nearest neighbour molecules to the substrate group) as suggested by Koshland (1962). For simple nucleophilic reactions at least, the opposite extreme will be reached when reaction is complete. So a comparison of EM’S derived from the rate constants for intramolecular cyclization and displacement processes with the “thermodynamic EM’S” derived from the equilibrium constants for the same reactions could be instructive. Few relevant data are available. Both equilibrium and rate constants have been measured for very few reaction series in solution, but comparisons are possible for lactone and thiolactone formation, and for a few anhydrideforming reactions (Tables 4 and 5). For lactone formation (Table 4) the EM for the rate process is of the same order of magnitude as that derived from the equilibrium constant data, and in some cases actually exceeds it (though only in one case by an amount clearly greater than the estimated uncertainty which is nominally a factor of 4 for these ratios). Lactonization generally involves rate-limiting breakdown of the tetrahedral intermediate, and the transition state is expected to be late and thus close in structure to the conjugate acid of the lactone. Neutral sulphur and oxygen nucleophiles of similar structure react with carbonyl groups at similar rates (Jensen and Jencks, 1979); the position of the transition state for thiolactonization is therefore expected to be similar. The comparisons of EM possible for three compounds in Table 4 show that the EM,/EM,, ratios are somewhat smaller for thiolactonization, by factors of 3 and 9 for the two compounds where all four EM’S can be estimated. Omitted from Table 4 are Hershfield and Schmir’s data (Tables B.l, 1&13 and B.2, 28-31) for the lactonization of substituted coumarinic acids. The EM,/EM,, ratios calculated from their data (given in Tables B.l and B.2) fall in the range 1 - 4 x lo-‘, and thus differ sharply from the ratios in Table 4. This is a consequence of the surprisingly high equilibrium constants for lactonization. These were calculated (Hershfield and Schmir, 1973a,b) from rate constants for the hydroxide-catalysed lactonization (which is apparent as a pH-independent reaction for very reactive systems). Though the procedure used appears to be valid, these equilibrium constants differ substantially from those measured for the acid-catalysed reactions, although no direct comparison is possible for any one compound. The second relevant set of data is for the formation of the anhydride from substituted succinic acid derivatives. Equilibrium constants for the formation of the anhydride from the acid are available for the various methyl-substituted compounds (Table A.l) and the derived EM’S are compared in Table 5 with those for intramolecular nucleophilic catalysis in the hydrolysis of half-esters

EFFECTIVE MOLARlTlES

203

TABLE4. Comparison of kinetic and thermodynamic EM’S for lactonization and thiolactonization reactions‘

x=o Compound

n

HX

CO,H

n HX

CO,H

x=s

EM,

EM,

EM,/EM,,

88

80

0.91

159

117

0.74

-

-

-

Data from Tables B . l , 2 and C.l, 2

EM,

3.7

X

-

lo3

EM,

EMJEM,,

384

0.1

-

-

9.5 x i(r 4.7 x 103

4.9 x

10-2

ANTHONY J . K I R B Y

204

TABLE 5 Comparison of kinetic and thermodynamic EM’S for anhydride-forming reactions‘ Anhydride

4

EMAb

EM,

EM,/EM,

EMBC

EM,/EM,

1.9 x 10’

5.1 x lo4

0.26

5.1 x 104

0.26

1.1 x lo6

1.3 x 10’

0.12

1.3 x 10’

0.12

2.7 x lo6

5.9 x 10’

0.22

1.2 x lor 1.6 x 10’

0.04 0.06

6.7 x lo6

1.2 x lo6

0.18

4.6 x 10’

0.07

3 x 10’

6.6 x lo6

0.02

3.7 x

0.01

2.0 x 1 0 7

4 x 10-3

6.7 x lo6

1.5 x 10-3

-

-

109

>o.s

0

Go 0

Go 0

6 0 0

go go

106

0

4.6 x

109

0

~ 1 . x7 1 0 9

0 ~~

a

~

Data from Tables A.l, A.2 and A.3 Derived from rates of cyclization of succinamic acids Derived from rates of cyclization of monophenyl succinate anions

205

EFFECTIVE MOLARlTlES

and half-amides of the same succinic acids. In both cases the transition state is thought to be the breakdown of the tetrahedral addition intermediate to form the anhydride (8). Furthermore, the transition state is expected to be late in

(8) 0

0

0

each case, at least for the unsubstituted succinic acid derivatives (from linear free energy relationship data and from consideration of the reverse reaction which involves the addition of an amine or aryloxide ion to the anhydride). Though EM ratios are given for both reactions, the data are not independent. The EM’S for the amide hydrolysis are based on a value (EM = 5.1 x lo4 M) for the succinamic acid reaction which is assumed to be identical with that for the hydrolysis of monophenyl succinate monoanion. However, both sets of data show similar behaviour. The EM’S for the rate processes, initially smaller by less then an order of magnitude than those for equilibrium anhydride formation, increase much less rapidly with increasing methyl substitution, so that the EM ratios decrease with increasing EM. This behaviour is reasonably interpreted in terms of a gradual change in the position of the transition state from a structure rather close to that of the anhydride to one with the breaking of the bond to the leaving group less far advanced. This process alone will produce a somewhat looser transition state, but, since the effect of methyl substitution is clearly to favour ring closure, the breakdown of the tetrahedral intermediate to regenerate starting materials must be substantially less favourable in the tetramethylsuccinic acid derivative. In the extreme case, therefore, a change of rate-determining step is possible to the formation of the tetrahedral intermediate. Although we can make some sense of EM ratios by discussing them in terms of varying transition state structure, the data so far available do not require this approach which must be considered only tentative at this stage. Equilibrium and kinetic EM’S for many more reactions are required before it will be possible to decide whether they contain useful information about transitionstate structure. It is to be hoped that it will rapidly become normal practice to attempt an estimate of the effective molarity as part of any quantitative work on intramolecular reactions. THE FORMATION OF SMALL RINGS

It is well-known that three-membered rings are readily formed by the cyclization of 2-haloalkyl derivaties of various nucleophilic species. Effective

206

A N T H O N Y J. K I R B Y

molarities for these reactions are difficult to obtain, but a useful range of data is available for the formation of epoxides (Table B.4) and aziridines (Table D.3). The EM'S for these two reactions are strikingly different; where direct comparison is possible the EM for the formation of the epoxide is 100-1000 times greater than that for the corresponding aziridine. It is likely that this factor reflects a fundamental difference in the nature of the nucleophilic centres concerned. This difference is responsible also for the wide differences in the relative rates of formation of three and five-membered rings containing differing hetero-atoms noted by Bird and Stirling (1973). These authors showed that the formation of the episulphonium ion from 2-chloroethyl p-tolyl sulphide (9) is actually faster than the formation of the corresponding five-membered ring from p-tolyl-S(CH,),CI. The EM for the

formation of ethylene oxide from the 2-chloroethoxide anion, on the other hand, is 24 times smaller than that for the formation of tetrahydrofuran from Cl(CH,),O-, and for the formation of the corresponding nitrogen heterocycles the ratio is nearly 500 (Table 6). The ready formation of the episulphonium compound is reasonably explained in terms of the directionality and polarizability of the non-bonded electron-pairs of sulphur, a soft nucleophile which naturally forms bonds at angles close to 90". We may presume that the directional requirements of the nucleophilic orbitals of first-row elements (N, 0) are stricter, and that this factor shows up most clearly in a situation (the formation of a three-membered ring) which makes extreme demands on orbital flexibility. A similar explanation allows us to rationalize the differences in EM for the formation of epoxides and aziridines (Table 6). The three covalent bonds to neutral nitrogen define the orientation of the non-bonded electron-pair so that an amine nucleophile has rather specific directional requirements. An alkoxide anion, on the other hand, has three degenerate orbitals on the oxygen atom, which makes for much greater directional flexibility in cases where this is needed.4 The need is clearly greatest during the formation of a three-membered ring and presumably disappears entirely for intermolecular nucleophilic attack. Thus a simple prediction arising from this explanation is that the effect will diminish with decreasing demands on directional flexibility, for example, with increasing size of the ring formed.

'Compare the flexibility of the geometry of hydrogen-bonding to the non-bonding electron-pairs of neutral oxygen elicited by the demands of crystal forces (Donohue, 1968)

207

EFFECTIVE M 0 LAR I TI ES

TABLE6 EM’S for the cyclization of cuhalogenoamines and alkoxides EM Compound B.4.1 D.3.1 B.5.1 D.3.14 B.5.4 D.3.17 B.5.9 D.3.22

Ring size, n 3 3 4

CI(CH,),- ,O- Br(CH,),- ]NH, 2.5 x 103

6 6 03

15

170

0.2

20

7 x 103

8.6

100

2.8

4

4 5 5

EM,-/EM,,,

6 x lo4 280

1’

I, Since EM’S are based on a common intermolecular reaction for each series, for which EM is defined as 1 (1 M standard state) this ratio is unity by definition. In fact EM’S for the formation of very large rings have been measured for both series and approach 5 x lo-, in each case, though with considerable fluctuations for particular ring sizes (Tables B.5, compounds 24-34, and D.3.24-27)

The data available for the cyclization of cuhalogenoalkoxides and amines (summarized in Table 6) show clearly that the superior reactivity of 0-over neutral N is indeed a function of the size of the ring formed; it falls off monotonically as angle strain in the product, and thus also in the transition state, decreases. These results are thus consistent with an explanation in terms of the differing directionality of the orbitals of the nucleophilic centre. Other relevant data are the rates of the base-catalysed cyclizations of N-o-halogenoalkylsulphonamides, p-CH,C,H,SO,NH(CH,),CI, where the nucleophile is a nitrogen anion having only two covalent bonds to the nucleophilic centre. Although accurate EM’S for these reactions cannot be calculated, the relative rates of cyclization (1 :7.4 x lo-’ :4.4 x for the formation of three-, four- and six-membered rings respectively) indicate that the formation of the three-membered ring is relatively more efficient than for neutral amine cyclizations (Bird ef al., 1973). For cyclizations where the nucleophile is a carbanion the three-membered ring is also formed more rapidly than the five, at least in some cases (Knipe and Stirling, 1967, 1968). Here the electron-pair involved occupies the n-bonding molecular orbital of the delocalized a-keto or a-sulphonyl carbanion and cannot directly be compared with the harder, localized oxygen and nitrogen cases. It would be interesting to assess the relative effects of alkyl substituents vs. protons on the directional flexibility of amine nucleophiles. Data are available

208

ANTHONY J KIRBY

(Table D.3) for aziridine formation from dialkyl 2-chloroalkylamines. The EM for the cyclization of Me,N(CH,),CI (D.3.4) for example is 1.3 M, significantly smaller than that for the reaction of the parent compound (D.3.1). The corresponding figure for the diethylamine derivative (D.3.6) is much greater (200 M), however; clearly, much larger effects come into play here. The influence of alkyl substitution on the efficiency of cyclization is a complex subject and is discussed in the next section. 5

Effects of substitution on the E M for ring-closure reactions

When a cyclic compound is in equilibrium with an open-chain derivative it appears to be the almost invariable rule that alkyl substitution favours the ring form (Hammond, 1956; Eliel, 1962). Many of the EM'S given in the tables (see in particular Tables A.l and B.l) support this conclusion, and many more show that it extends also to transition states leading to cyclic compounds because the generalization is almost as strong for the effects of alkyl substitution on the rates of ring-forming reactions (see Tables A.2, A.3, B.2, B.4, B.5 and B.6 for examples). As a rule effective molarities based on equilibrium constants are larger than those derived from rate constants for the formation of a given cyclic compound (see Tables 4 and 5) as expected if the relative stabilities of ground states and products are the dominant factor. However, the effects of alkyl substitution on rates and equilibria clearly parallel each other in most cases. With the considerable number of relevant EM'S available in the tables which allow direct comparisons of the efficiency of cyclization reactions of different types, it is of interest to examine the effects of alkyl substitution on ring-closure reactions in the light of the explanations currently available. T H E THORPE-INGOLD

EFFECT

Historically the first of these explanations has become known as the Thorpe-Ingold effect (Beesley ef al., 1915; Ingold, 1921). The external angles between bonds on the carbon atoms of small rings are increased over the normal tetrahedral value, leading to decreased non-bonded interactions between geminal exocylic groups compared with the situation in open-chain compounds. The point is illustrated by the x-ray crystallographic data shown in Table 7 (taken from Kirby and Lloyd, 1976b). The angle between the two bonds to the carboxyl carbons of malonic acid is l l O o , close to the normal tetrahedral angle of 109'28'. When this angle is external to a three-membered ring, as in cyclopropane-1,l-dicarboxylic acid, it is increased to 118.4'. Conversely, the corresponding angle in dimethylmalonic acid is only 106.2'. Apparently the two methyl groups force the carboxyl groups into closer proximity, presumably by occupying space into which they would otherwise spread out.

EFFECTIVE M O L A R I T I E S

209

TABLEI Effects of gemdialkyl substitution on bond angles' Compound

,CO,H CH, a 'CO,H

Angle a

1100

'Taken from Kirby and Lloyd, 1976b

Consider now what happens when the two carboxyl groups react to form a small ring, for example the anhydride. The angle between the carboxyl carbons must be reduced much further, perhaps to around 90°, in the product and in the transition state leading to it. Compared with malonic acid itself, this process has less far to go in the dimethyl compound because the two alkyl groups have already forced the carboxyls part of the way towards each other. The observed diminution in bond angle caused by the introduction of the two alkyl substituents thus specifically favours the formation of the small ring. The Thorp-Ingold effect is expected to operate specifically in reactions in which small rings are formed. There is no reason why diminution of a potential internal angle of a ring should assist ring-formation when the ring angles are normal. Yet alkyl substitution favours the formation of five- and six-membered rings also. The presumption is that different factors are dominant in these cases (see below), so presumably a different sensitivity to alkyl subsitution is to be expected for the formation of smaller compared with larger rings. Specifically, we should expect the Thorp-Ingold effect to be particularly evident for the formation of three- and four-membered rings. Futhermore, because the energies involved in changing bond angles (vibrational) are greater than those involved in changing conformation (rotational), it is a reasonable expectation that the effects of alkyl substitution on the formation of smaller rings should be larger than those for the formation of rings with little or no angle strain. Bird et al. (1973) could find no evidence that the effect is greater for the formation of a three- compared with a five-membered ring but the data in Table 8 suggest exactly this.

N A ..

0

TABLE8 The gem-dialkyl effect as a function of ring size: relative EM'S for the formation of small rings

Ring size

Reaction and relative EM"

LC'

&Cl

0-

O--2

l(2.5 x [email protected])

4 x l(r(1VM)

400 (lo6M)

2.8 x i(r (7 x 109 M)

3-L 425 (1700 M)

D

1

z

VOh

0

03 OAr i (5.1 x 10' M)

2.3 (1.2 x 1oJ M)

131 (6.7 x 106 M)

W

<

5’

Succinic acid $ anhydride i(i.9 x 1 0 5 ~ )

HO,C )(/CO,H 2 4 x 10‘ (4.6 x lo9M)

14 (2.7 x lo6M)

18 (2.1 x 103 M)

3.6 (800 M)

With one exception (see note d) the figures quoted for each series are EM’s relative to the unsubstituted compound. The actual EM’s are given in parentheses * Data from Table B.4, cornpounds I, 5,6 and 9 Data from Table B.5.1-3 Data of Brown and van Gulick (1956). The figures quoted in this case are relative rate constants, as given by the authors. These were measured in two different buffer solutions at three different buffer ratios altogether, and data for different compounds do not always refer to the same conditions. The rate constants have been corrected by the authors for pH differences, but no values of pH are given, nor have pK,-values been measured. The data are not therefore adequate for the calculation of EM’s even of the lowest category of accuracy, and the figures given cannot be relied on to give more than an indication of relative orders of magnitude of reactivity Data from Table A.2, compounds 1,4 and 9 ’Equilibrium data for the formation of the succinic anhydride from the acid; Table A.l, compounds I, 3 and 6. The 2,2dimethylsuccinic acid could react either way with the electrophilic CO,H group either the one next to the tertiary centre or the other. It is assumed that the latter will be attacked more readily by the neighbouring carboxyl group 8 Data from Table A.2, compounds, 21,22 and 27

212

A N T H O N Y J KIRBY

Table 8 contains the available data on the gem-dimethyl effect on EM’S for the formation of small rings. Some results of Brown and van Gulick (1956) on the cyclization of 4-amino- 1-bromobutanes have been included, although they are not considered accurate enough for EM calculations because of the lack of suitable data for the formation of a saturated five-membered ring. The data have been arranged vertically according to the size of the ring formed and horizontally according to the position of substitution relative to the nucleophilic centre. Thus the first column lists the unsubstituted (reference) reaction, the second column compounds with the gem-dimethyl group next to the nucleophilic centre, and the last column compounds where it is next to the electrophilic centre. (A trivial exception is the 3,3-dimethylglutarate ester which should in principle occupy a separate column but does not simply to save space.) Arranged this way, the data show that the effect of introducing two geminal methyl groups into any given position relative to the nucleophilic centre (read down any column) has the largest effect on the formation of the smallest ring. The arrangement of the data is intended to be strictly logical rather than to prove the point in question, but almost any alternative arrangement would lead to the same conclusion. This is that the introduction of two geminal methyl groups can have a very large effect on the formation of an epoxide, a fairly large effect on the formation of a four-membered cyclic ether, and relatively smaller effects on the rates of formation of five- and six-membered rings. Apart from this generalization, the point which emerges most clearly is that the magnitude of the gem-dimethyl effect depends very much on the position of substitution. If the two methyl groups are p to the electrophilic centre, which thus becomes a neopentyl position, the effect may be sharply reduced. Thus the formation of the pyrrolidine from 4-amino-2,2-dimethyl-1-bromobutane (Table 8) is actually slower than that of the unsubstituted compound, and the formation of the symmetrical dimethyloxetane is only twice as efficient as that of oxetane itself. A similar comparison is possible for the cyclization of Me,NCH,CMe,CH,CI which is only nine times faster than that of Me,N(CH,),CI at 5 6 O in 80% aqueous ethanol (Grob and Jenny, 1960). On the other hand, the fact that it has the configuration of a neopentyl halide does not prevent the corresponding /3-chloroethoxide (B.4.5) from forming the epoxide very rapidly. So we may conclude that intramolecular nucleophilic attack on the neopentyl centre becomes progressively less unfavourable as the size of the ring being formed decreases. For amine cyclizations it is possible to introduce gem-dialkyl substitution at the nucleophilic centre, and the data in Table 9 suggest that a similar but reduced effect may operate in this position also. The accuracy of the EM’S given in Table D.3 is not such that absolute magnitudes are very significant, but the relative magnitudes in this series are reliable since the rate constants on

213

EFFECTIVE M O L A R l T l E S

TABLE 9 The effect of N,N-dialkyl substitution on the efficiency of aziridine formation Amine

EM/M

D.3.1 H,N

*. -2

D.3.4 Me,N

1.3

owBr

D.3.6 Et,N -cl D.3.8

15

2000

1.5

which they are based come from the same source. The pattern of reactivity is very much that observed for substitution on carbon in similar cyclizations with the exception that the dimethylamino-compound is less reactive than 2-chloroethylamine. It is normal [see Tables A.l and A.2, and Brown and van Gulick (1956)l for the effects of alkyl substitution to increase with the size of the group concerned, and there is no doubt (see footnote to Table D.3) that the high EM for the diethylamino-compound is genuine. The data also illustrate the well-known decrease in the steric effects of two geminal ethyl groups when they are linked together in a six- and especially a five-membered ring. If the data of Table 9 represent a further manifestation of the Thorpe-Ingold effect, it must presumably be operating on the angle between the N-C bond and the axis of the lone pair orbital on nitrogen. There is nothing in the data to suggest that the effect of two alkyl groups is greater than would be expected for the combination of the effects of two single substituents or indeed that geminal substitution is necessarily more effective that vicinal dialkyl substitution. This could be the case for the formation of three- or four-membered rings but we cannot be sure because sufficient data are not available. It clearly is not the case for the formation of some five-membered rings (Table 10). Although the data are again too few to support a generalization, the vicinal dimethylsuccinic acid derivatives cyclize at

A N T H O N Y J. KIRBY

21 4

TABLE10 Effect of geminal vs. vicinal substitution on EM'S for ring-closure reactions Ring size

Reaction and relative EM

Lcl

&CI O

0-

-

d

320 (8 x lo5 M)

s (4 x

I

I (5.1 x 104 M)

104

4 x l(r ( lo8 M)

400 ( lo6 M)

M)

2.5 (1.3 x l o 5 M)

Hydrolysis of succinamic acid

0-

2.4 (1.2 x 105 M)

CONHPh HO,C

I(5.1 x 1 P M ) Succinic acid + anhydride

&C02H H02C 5.8(1.1 x 106M)

1

n

2.5 (1.3 x l o 5 M)

P

O- o P 0 2 - O R I (1.2 x 1 0 4 ~ )

a

1.9(2.5 x 104M)

Data from Table B.4, compounds 1,3-6 Data from Table A.2, compounds 1-7 Data from Table A.3, compounds 1-5 Data from Table A . l , compounds 1 - 4 Data from Table B.6, compounds 3-6

280 (3.6 x lo6 M)

215

EFFECT1VE M OLA A IT1ES

Reaction and relative EM

C0,Ar

-0 ,c&Co2Ar

3.1 (1.6 x lo5M)

-0,c

A C O N H P h HO,C 12 (5.9 x 105 M)

H02C 14 (2.7 x lo6 M)

+

9.0 (4.6 x 105 M)

9.0 (4.6 x los M)

CON HPh

HO,C

B ( 1 . 2 x 106M)

5.7 (2.9 x 105 M)

HO,C+/02H

35 (6.7 x 106 M)

6.1 (8 x IVM)

216

ANTHONY J KIRBY

least as efficiently as the gem-dimethyl compounds in most cases. The lower EM’S for the cyclization of derivatives of meso-dimethylsuccinic acid are expected because of the eclipsing interactions between the vicinal methyl groups which develop in the transition state and the anhydride, and the same factor may account for the low EM for the hydrolysis of cyclohexyl erythro3-hydroxy-2-butyl phosphate (Brown and Usher, 1965). EFFECTS ON THE FORMATION OF LARGER RINGS

The magnitude and direction of the effects of alkyl substituents on the efficiency of formation of six-membered rings are generally satisfactorily explained by the proposals of Allinger and Zalkow (1960). The enthalpy of ring-closure is more favourable for alkyl-substituted n-hexanes because of the increased number of gauche interactions in the open-chain compared with the cyclohexane product. The entropy of ring-closure is more favourable also, because branching reduces the rotational entropy of the open-chain form significantly more than that of the ring which has built-in restrictions to internal rotation. Calculations of the expected magnitude of these effects for a group of methyl-substituted cyclohexanes gave good agreement with the known free-energy differences between open-chain and cyclic forms in the gasphase. These differences are large enough to account for all the effects of methyl substitution on the EM’S for the formation of five- as well as sixmembered rings calculated in Tables 8 and 10. There remain to be explained cases where very large effective molarities are observed for the formation of five-, six- or seven-membered rings. Most of these cases involve more or less rigid systems and are readily explained in terms of relief of ground-state strain (see below). A small number, however, involve conformationally mobile systems. Eliel (1962) notes cases where two gem-dimethyl substitutions lead to dramatic effects on the equilibrium constant for the formation of the anhydride from certain dicarboxylic acids. Quantitative information is available for one of these reactions; the formation of tetramethylsuccinic anhydride from the acid has an EM 2.4 x 10‘ times greater than that for the formation of succinic acid itself (Table 8). The rate constants for the formation of the anhydrides from the aryl ester and amide show similar effects (A.2.9 and A.3.7, respectively), and there is some preparative evidence that the four methyl groups of ay&,d-tetramethyladipic anhydride confer similar remarkable stability on the seven-membered ring (Farmer and Kracovski, 1927). It is possible that hydrophobic forces may come into play for heavily alkylated systems in water, favouring, for example, the fully eclipsed tetramethylsuccinic anhydride because the more compact hydrocarbon part of the system disrupts the water structure less than in the

EFFECTIVE M O LA A IT1ES

217

diacid. Hydrophobic forces will of course be superimposed on the factors considered by Allinger and Zalkow, whose calculations refer to the gas phase, and probably also account for the surprisingly high EM’S for the formation of very large rings (see the last entries in Tables B.5, D.l and D.3.27). In fact there is some evidence that the effect of four methyl substituents can be explained without invoking special effects. Blagoeva et al. (1979) have shown that the rate and equilibrium constants for the formation of dihydrouracils from Pureidopropionic acids ( 10) are correlated by steric strain energies estimated from the enthalpies of formation of model hydrocarbons. The steric strain energies P (or AP, representing the strain between two fragments of the hydrocarbon) were obtained by a procedure due to Istomin and Palm (1972). The correlation with AP is fairly good (r 30.965) for the

rates of cyclization of ten Pureidopropionic acids, and holds also for the data of Tables A.l and A.3 for the formation of succinic anhydrides and the hydrolysis of succinanilic acids ( r = 0.992 and 0.993, for five and six data points respectively). The latter set includes the hydrolysis of tetramethylsuccinanilic acid (A.3.7), which would be expected to show a substantial positive deviation from the correlation line if a hydrophobic effect were superimposed on other effects in this case. THE RELIEF OF GROUND-STATE STRAIN

The large effects of gem-dialkyl substitution on the efficiency of formation of three- and four-membered rings were attributed above to the diminution in bond angle caused by the introduction of the two alkyl substituents into the chain. Ring formation is favoured because the two alkyl groups have in effect forced the reacting groups part of the way towards each other in the ground state. The extra driving force is presumed to result from non-bonded interactions both between the cyclizing groups and the two alkyl substituents and also between the two alkyl groups themselves, all of which are reduced when a small ring is formed with its naturally small internal angle. Thus strain in the ground state is relieved in the product and in the transition state leading to it. Similar effects are observed on the formation of larger rings in rigid systems. A system where the interpretation leaves little room for doubt is di-

218

A N T H O N Y J. KIRBY

methylmaleic acid, which exists in acid solution predominantly as the cyclic anhydride [191. The EM for reaction (1 1) is estimated as 2.7 x 1OI2 My and 0

[ 191

similar extraordinarily high EM'S are found for the rates of formation of the anhydride from the half-esters (Table A.2) and half-amides of this acid. Comparative data for several related amides are summarized in Table 11. The unsubstituted maleamic acid is already a very reactive system, with an EM almost identical to that found for the hydrolysis (via the anhydride) of phthalamic acid (A.3.9). The introduction of one and then two methyl groups increases the EM by factors of 30 and 1.5 x lo4 respectively, but linking the substituents in a ring (compounds A.3.18-20) dramatically reduces the effect, by a factor of over lo9 for the cyclobutene derivative. Since all the groups involved lie in the same plane, conformational effects are excluded. The clue to these large difference in reactivity, which reflect differences in the enthalpy of activation (Kirby and Lancaster, 1972), is found in the angles (labelled a a n d P in Table 11) between the double bond and the reacting groups. These are much larger in the trisubstituted olefin than the normal 120" angle expected for sp*-hybridized carbon, presumably because non-bonded repulsion between the carboxyl and amide groups is relieved by increasing these angles, the carboxyl group in particular moving into closer proximity to the vinylic hydrogen atom. In a dialkylmaleic acid derivative this position is already occupied by an alkyl group which has its own steric requirements, and angles a and P are both sharply reduced to little more than 120O. Since the corresponding angles in the anhydride are smaller still, the non-bonded interactions between the two alkyl groups are reduced still further by ring-formation since bond angles exocyclic to the five-membered ring are closer to 130" (cf. compound A.3.19). So the picture for a dialkylmaleic acid is of considerable strain in the ground state [evident from a close inspection of the three-dimensional structure (Roberts and Kennard, 1973) as significant deviations from planarity about the double bond, including a dihedral angle of 8" between the bonds to the carboxyl and amide groups1 which is relieved in the cyclic product and the transition state leading to it.5 In compounds A.3.19 and especially A.3.20 angles a and B open out and are even larger than in the monomethyl derivative (A.3.13). Larger changes of bond angle are thus required to effect cyclization which has now become even less favourable because the expansion of the incipient exocyclic angles is inhibited by the small ring already present.

219

EFFECTIVE MOLARlTlES

TABLE11 Comparative data for the hydrolysis of substituted maleamic acids Compound

EM/M

Angles&$

A.3.12 L O N H M e

‘gO,H

2 x 109

A.3.13 Y C O N H M e

\CO,H

A.3.17 R

R

x

6 x 1O1O

126.8, 131.7O

3 x 1013

121.0, 121.70b

CONHMe CO,H

A.3.18 e C O N H M e

u C 0 , H

1 X 10’’

127.7, 131.5O A.3.20

dCONHMe ‘CO,H

sx

103

132.1, 133.40e

Data given by Kirby and Lloyd ( 1976) EM for R = Me, artgles for R = isopropyl; the EM is not much affected by the substitution Angles are for the diacid (Bellus et al., 1974)

Similar explanations almost certainly account for the very large effective rnolarities found for lactonization of the hydroxy acids B.1.13, B.2.16 and B.2.25 (Table 12). All these compounds have the basic tetrasubstituted ethylene (here o-phenylene) structure found in the dialkylmaleic acid system further destabilized by substituents in the 3 and 6 positions of the benzene ring which also act to prevent bond angle spreading of the two inner substituents. (The effects of 3- and 6-substituents on this type of cyclization reaction are well known, and are shown for example by the range of EM’S for compounds

ANTHONY J. KIRBY

220

TABLE 12 Effects of alkyl substitution on EM'S for lactonization of hydroxy acids Substituted compound

B.1.13

&02H

\

Model compound

B.1.9

\

/

H EM 2 x 1 0 1 3

B.2.16 H : &

m 0 H ,

/

EM 3.7 x 10"

B.2.9

ErH

EM > l o 1 *

EM 9 x 104

EM 4 x lo4

EM 7 x 10"

B.2.9-12.) The interaction between an o-methyl group and an qa-dimethyl-substituted chain is particularly severe, and undoubtedly leads to restricted rotation about the ring-chain bond (see Lomas and Dubois, 1978). This is not itself a major source of high effective molarities, however, as shown by the moderate EM'S for compounds like [20l and [211 which have naturally restricted conformations (Danforth et al., 1976). In lactonization of B.2.25 and the related compounds B.2.24 and 23, ground

B.2.26

B.2.21

EM 8 x lo6

EM 5.3 x lo8

I201

[211

EFFECTIVE MOLARITIES

22 1

state strain is implicated by force-field calculations (Winans and Wilcox, 1976) and by the observation of a large steric isotope effect (Danforth ef al., 1976). Thus when the geminal cr-methyl groups of B.2.23 (EM 1.2 x 10") are replaced by CD, groups (12), the rate of lactonization is reduced by nearly 10%. The x-ray structure of the alcohol derived from B.2.25 also shows

Q02H

d

CD, CD,

mo \

kh6/kd6= 1.09

(12)

CD, CD3

B.2.23-dG

severe distortions of bond lengths and angles. For example, the benzene ring has internal angles ranging from 114.3 to 125O, and bond lengths as high as 1.428 A, compared with the normal value of 1.39 A. There is a severe van der Waals interaction between one a-methyl and the methyl group in the ortho-position (C-C distance as small as 2.86 A), and the a-carbon bearing the two methyl groups is 0.17 A out of the plane of the ring, All these distortions, though they do not all disappear, are substantially relieved on cyclization, as shown by an x-ray study by the same authors (Karle and Karle, 1972)of the corresponding lactone. Thus in two systems showing very high effective molarities for the formation of five- and six-membered rings there is strong structural evidence for substantial strain in the ground state. The other two most reactive systems (B.1.13 and B.2.16) are intermediate in structural type, and undoubtedly owe their high reactivity to similar factors. Such high EM'S (> 1OloM)are scarcely to be expected for the formation of three-, or especially four-membered rings, because of the angle strain associated with the small ring of the product, and they are not found in any system where the open-chain form has significant conformational flexibility. An effective molarity of 1O'O M or more may therefore be taken as prima facie evidence for strain in the ground state which is relieved in the cyclic product. An important question is how far these very large EM'S are relevant to the problem of the high efficiency of enzyme catalysis. Ground state strain is built into a molecule when it is synthesized, and organic chemists are very adept at making highly strained compounds. The equivalent process in an enzyme reaction is the formation of the enzyme-substrate complex, and the possibility

222

A N T H O N Y J. KIRBY

that reacting groups might be forced closer together than the sum of their van der Waals radii, or that bond angles of the substrate might be deformed on binding, might appear to open up exciting possibilities for the theory of enzyme catalysis. Recent opinion, for example calculations by Levitt (1974), does not generally support this idea. Proteins are not rigid structures, and from estimates of the maximum force an enzyme can be expected to exert on a substrate he concludes that “small distortions of substrate . . that cause large increases in strain energy cannot be caused by binding to an enzyme”. There is little doubt that this conclusion is correct, and that enzyme-substrate binding cannot cause substantial strain of the sort described in this section (Fersht and Kirby, 1980).

.

ORBITAL STEERING

A great deal of interest was stimulated by Koshland’s suggestion (Koshland et af., 1971) that the high efficiency of enzymic and some intramolecular reactions depends on the correct orientation of the reacting orbitals. The chance of a random collision producing this correct alignment of orbitals was considered small, giving the prealigned reaction an advantage estimated to be of the order of lo4 (Storm and Koshland, 1972a,b). The concept of “orbital steering’’ has been extensively critized (for a concise history, see Gandour, 1978), generally because the potential effects have been considered to be overestimated. Certainly some reactions do have reasonably specific orientational requirements: an example is the S,2 reaction-there are no examples of 0or N-C-6n in the tables, no doubt because the nucleophile cannot get close enough to an “in-line” relationship with the leaving group when they and the central carbon atom all have to be accommodated in a six-membered ring. On the other hand the ease of epoxide formation shows that one of the components is allowed a great deal of latitude in this reaction. The data in the tables can generally be interpreted satisfactorily without invoking such orientation effects. This is not to say that they do not exist at all, but simply that they must be relatively small. The major difficulty in identifying any small effect is the elimination of all other possibilities. Storm and Koshland (1972ab) have made the best attempt to do this in their discussion of the relative rates of lactonization of the series of hydroxy and thioacids B.2.1-9 and C.2.1-5, but these rates were found to parallel the equilibrium constants for the lactonization, and it seems probable that the dominant effect controlling reactivity in these systems-and not corrected for-is the relief of groundstate strain discussed above.

EFFECTIVE MOLARlTlES

6

223

Tables of effective molarities

As we have seen (Section 4, p. 19 1) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis; the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM’S for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. Intramolecular general base catalysed reactions (Section 11, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [41). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [51), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. One class of reaction, conventionally designated as intramolecular general base catalysis, which is actually unimolecular is enolization catalysed by a neighbouring basic centre [221. It might be thought that this reaction has as

[221

1231

L241

much in common with an intramolecular nucleophilic substitution [231 as with other intramolecular general base catalysed reactions [241, but the important factors are that cyclization cannot occur and that displacements at a hydrogen centre fall naturally into the same class. Section I11 (Table H), intramolecular general acid catalysis, is the smallest because this mechanism is less common and because where it is observed (mostly in acetal chemistry) the corresponding intermolecular reactions often cannot be detected.

224

ANTHONY J. KIRBY

NOTES O N TABLES A-H

Abbreviations A = carboxylic acid group E = ester group M = amide group C =tetrahedral carbon P" = tetrahedral phosphorus bearing (4 - n) oxygens bound only to P (e.g. diester phosphorus is P2). EM = effective molarity of neighbouring group Conditions Data refer to reactions in buffered aqueous solution unless otherwise indicated. Rate constants These are the ones given in the reference cited, converted if necessary to s-l. Temperature P C .

EM Details of calculations (see text) are given in full except where these are given by the original authors. Accuracy Maximum estimated errors are: a, +lo%; p, within a factor of 2; y, within an order of magnitude.

EFFECTIVE MOLAR IT1ES

225

I EFFECTIVE MOLARITIES FOR CYCLIZATION REACTIONS

(TABLES A-D)

A

REACTIONS OF THE CARBOXYLIC ACID GROUP

A. 1 Equilibrium data for anhydrideformation: from succinic, maleic and phtha lic acids"

Y 0

Acid A.l.l A.1.2 A.1.3 A.1.4 A. 1.5 A.1.6 A.1.7 A.1.8 A.1.9 A.l.10 A.l.ll A.1.12 A.1.13 A.1.14 A.1.15 A.1.16

K

T

7 x 10-6 60 4.2 x 10-5 60 1.0 x 10-4 60 2.5 x 10-4 60 60 (0.01 0.17 60 dl-2,3-Diethyl-2,3-dimethylsuccinic 3.4 60 meso-2,3-Dkhyl-2,360 1.o dimethylsuccinic Tetraethylsuccinic 10 60 dl-2,3-di-isopropylsuccinic (0.1 60 6 dl-2,3-di-t-butylsuccinic 60 1,2,-Diethyl-cis-cyclopropane(0.01 60 dicarboxylic 1,2-Di-isopropyl-cis-cyclo60 0.30 propanedicarboxylic 0.60 Norbornane-endo-cis-2,360 dicarboxylic 2-Methylnorbornane-endo-cis0.60 60 2,3dicarboxylic 0.30 Bicyclo[2.2.2loctane-cis-2,360 dicarboxylic Succinic Methylsuccinic 2,2-Dimeth y lsuccinic dl-2,3-Dimethylsuccinic Trimeth ylsuccinic Tetramethylsuccinic

A.1.17 A.1.18 A.1.19 A. 1.20

PhthalicC 3,6-Dimethylphthalic 3,6-Diethylphthalic 3,6-Di-iodophtalic

( 5 x 10-3 0.20 1.5 (0.1

25 60 60 60

A.1.21 A.1.22 A.1.23 A.1.24 A.1.25 A. 1.26

Dimethylrnaleic Methylethylmaleic Diethylmaleic Cyclohexene-1,2-dicarboxylicd Di-isopropylmaleic Di-t-butylmaleic'

5.3 4.3 3.2 4.7 25 ca. lo2

20 20 20 20 20 25

EMb

Accuracy

1.9 x 105 1.1 x 106 2.7 x lo6 6.7 x lo6 (3 x 10' 4.6 x 109 9.1 x 1O1O 2.7 x 1O1O

a a a a a a a a

2.7 x 10I1 (3 x 109 1.6 x loL1 <3 x 108

a a a a

8 x 109

a

1.6 x 1O1O

a

1.6 x 1O1O

a

8 x 109

a

x x x x

109 109 1O1O 109

B B B B

2.7 x 10" 2.2 x 10'2 1.6 x lo1, 2.4 x 10I2 6.7 x 1O1I 3 x 1013

B B B B B

(1.7 5.4 4.0 (2.7

Y

226

ANTHONY J. K I R B Y

, Eberson and Welinder, 197 1 bThe reference reaction used is the formation of acetic anhydride from acetic acid in water.

From the known values of AGO (15.70 kcal mol-’) measured by Jencks et al. (1966) and A H o (14 kcal mol-I) determined by Conn et al. (1942) and Wadso (1962) for its hydrolysis, the equilibrium constant for the formation of acetic anhydride can be calculated to be 2.0 x lo-’, at 20°, 3.1 x lo-” at 25O and 3.7 x lo-” at 60° See also Hawkins, 1975 Eberson, 1964 Aldersley and Kirby, unpublished

A.2

Intramolecular nucleophilic caiuiysis of ester hydrolysis by the carboxyl group ~~

~~~

Ester

Ref.

COO--E-Sx:

pK,

kOb8

T

EM’

Accuracy

Monoaryl succinates

A.2.1

4.30 -

1.42 x 1.42 x lo-’

25 25.3

5.1 x 10‘ -

P

4.3

1.55 x lo-’

25.3

5.1 x lo‘

P

4.3

4.0 x lo-’

25.3

1.3 x 10’

P

4.3

3.7 x 10-3

25.3

1.2 x 10’

P

e

5.9

5.33 x lo-’

30

1.6 x lo5

P

c*d

4.3

1.40 x lo-’

25.3

4.6 x 10’

P

e

&Ph

coo0

A.2.2

A.2.3

A.2.4

A.2.5

A.2.6

C0,Ar

c,d

XooC0,Ar

cad

xooC0,Ar

c.d

LooC0,Ar

EFFECTIVE M O L A R l T l E S

227

~~

Ester A.2.7

A.2.8

A.2.9

Ref.

1.38 x lo-'

25.3

4.6

10'

B

C*d

4.3

0.11

25.3

3.7 x lo6

P

=*d

4.3

0.21

25.3

6.7 x lo6

P

3.5

0.17 0.87 177

24.5 30 30

2.4 x 10' 1.3 x 10' 2.5 x lo9

Y a

24.5

3 x lo9

Y

kcooC0,Ar

Accuracy

4.3

c.d

C0,Ar

EM"

kob.

LooC0,Ar

T

pK,

X

xooA.2.10

f

r.h

COOAr

-

Y

&oo-g COO--E-Sx:

Monoaryl maleates andphthalates

0

A.2.12

.2.68

[LIlAr

a

3.3 x lo-'

COOH-E-Sx: Monoalkyl hydrogen maleates andphthalates

A.2.13

COOMe

'*'

3.37

2.7 x lo-'

3.3

6.7 x lo-'

100

109

Y

OZH

A.2.14

61.7

8 x 1Olo

Y

A N T H O N Y J. K I R B Y

228 Ester

Ref.

pK,

koba

T

EMa

Accuracy

39.5

1.5 x 10"

Y

Y

A.2.15

n

3.0

1.6 x

A.2.16

1.P

-

4.7

10-5

60

3 x 109

P

-

6.3 x lo-'

60

6 x 1O'O

-

2.2 x 10-2

39

4 x 10l2

-

1.8 x

39

5 x 10"

-

9.9 x lo-'

39

(5 x 1012)

A.2.17

A.2.18

C0,Et

A,,,,

C0,Me

0

x C O z H

)rOzH '

C0,Me

A.2.19a

COO--E--Sx Anion of A.2.19

Y Y

COW-E-6x:

Monoaryl glularates'

A.2.21

I

A.2.22

-0,c &CO,Ar

6.22 5.95

7.4 x lo-' 5.6 x lo-'

30) 30

220

B

6.20

2.7 x lo-'

30

800

B

EFFECTIVE MOLARlTlES

Ester

A.2.23

229

Ref.

R, = H, R, = Me

pK,

A.2.26 A.2.21 A.2.28 A.2.29 A.2.30 A.2.3 1 A.2.32 A.2.33

EM'

Accuracy

30

910

P

30 30

730 1.9 x lo3

P P

1.9 x 10-3

30

3.4 x 103

B

Y

6.34 6.63 6.77 6.54 6.21

1.3 x 1.0 x 1.0 x 1.5 x 1.8 x

lo-, lo-, lo-'

30 30 30 30 30

2.1 x 8.2 x 6.0 x 1.5 x 3.9 x

Y

6.55

1.2 x lo-,

30

1.2 x lo4

Qj-5

3.3 x lo-,

25

I Y

A.2.24 A.2.25

T

k,,,

R, = H,R, = Ph R, = H, R, = n-Pr R, = H, R, = i-Pr R, = R, = Me R, = R, = Et R, = R, = n-Pr R, = R,= Ph R, = Me, R, = Ph R, = Me, R, = i-Pr Me

I Y

Y

Y Y

Y Y

'

6.23 6.04 6.08 6.14

3.2 x 2.1 x 2.5 x 7.3 x

6.29

4.26

lo-' 10-4

lo-' 10-

lo-)

lo-,

lo3 lo3 lo3 lo4 lo3

9 x loL1

Y

POPh

0 COO--Edn: Acyl salicylates

&lo = %y 4.41 x lo-'

39

>13

B

qcoo-

25

2.6 x 10'

P

A.2.34

-2.4

OAc

COOH

3.11,4.6

1.62 x lo-,

2 30

ANTHONY J

Ester

Ref.

pK,

-

kobs

4.3 x

KIRBY

T

EMa

Accuracy

30

9.2 x 10'

B

The reference intermolecular reaction is the nucleophilic attack of acetate on phenyl acetate, calculated by Page (1973) from the data of Gold et al. (1971) by extrapolation (from measurements on aryl acetates which show measurable nucleophilic catalysis). But see notes g and h * Gaetjens and Morawetz, 1960 In 11% acetonitrile (Eberson and Svensson, 1972) Ar = 2-hydroxyphenyl (Eberson and Svensson, 1972) Ar =p-bromophenyl in 50% dioxan-water. EM calculated from kobs for p-bromophenyl succinate measured under the same conditions 'Ar = p-methoxyphenyl (Bruice and Pandit, 1960). Calculated from kobs for p-methoxyphenyl succinate measured under the same conditions and corrected for the observed pK, using B = 1.0 Bruice and Turner, 1970. Results were obtained from direct comparison of the intramolecular and intermolecular reactions under the same conditions, but without allowing for the difference in pK, from acetate or the fact that the intermolecular reaction in water is predominantly general base catalysed. (The two factors largely cancel out.) In dimethyl sulphoxide containing one mole of water. Both reactions are probably nucleophilic under these conditions 'Thanassi and Bruice, 1966 for 'Corrected for the difference in pK, from acetate using /3 = 1.0, and by a factor of 8.7 x the lower reactivity of phenyl benzoate compared with phenyl acetate. This calculation is that of Page (1973) and appears to be the best that can be done k A r =pmethoxyphenyl (Bruice and Pandit, 1960). The calculation (Page, 1973) is similar to is used for the lower that for phenyl phthalate (note J), except that a factor of 6.3 x reactivity of the unsaturated ester EM is assumed to be lo9 M for all phthalate esters, and 3 x lo9 M for all maleate esters Eberson, 1964. The reaction is eighty times faster than that of methyl phthalate under these conditions (using activation energy = 23 kcal mol-') " Hawkins, 1975a. The reaction is 150 times faster than for trifluoroethyl phthalate at 39.5' [using data of Thanassi and Bruice (1966)) for ethyl maleate = 3.07 x lO-'s-' Pekkarinen, 1957; khyd Lancaster, 1971 'Aldersley et al., 1974a EM is on the same scale as for aryl succinates (above), corrected for the increased pK, of substituted glutarates using p = 1.0 Ar =p-bromophenyl in 50% dioxan-water (Bruice and Pandit, 1960) " Conditions and leaving group as in f (Bruice and Bradbury, 1968)

'

EFFECTIVE MOLARlTlES

23 1

" In 20% dioxan (Hegarty et al., 1974). The reference reaction is nucleophilic attack by alkoxide ions on phenyl N-methyl-N-phenylcarbamate at 25O in water (Hutchins and Fife, 1973). The rate constant for bimolecular attack by an oxyanion of pK, 4.26 (3.6 x dm3 mol-I s-') is obtained by a long extrapolation of a two point Brmsted plot (which has the reasonable slope of 0.90) "Reference reaction is attack on 2,4-dinitrophenyl acetate by RCOO- of pK, 2.4 (k2= 3.3 x lo-' s-' based on a short extrapolation using p= 1.0: Jencks and Gilchrist, 1968). The reaction measured is the subsequent hydrolysis of the mixed anhydride; the observed value thus sets only a lower limit for EM (Fersht and Kirby, 1967b, 1968a) Fersht and Kirby, 1968b. Formation of the anhydride is rate determining here. The reference reaction is that of phenyl acetate with a carboxylate anion of pK, 3.11 (see note a ) Kemp and Thibault, 1968. The reference reaction is that of RCOO- with phenyl benzoate (see notej] 'pK not measured. A value of 3.7, equal to that measured for aspirin, is assumed for the calculation A.3 Intramolecular nucleophilic catalysis of amide hydrolysis by the carboxyl group

-iy

'C0,H Amide COOH-M-5x:

T

Accuracy

B

Succinamic acids

4.54

3.1 x

65

-

-

2.1 x 10-5 6.5 x lo-'

60 25

5.1 x 104

1.3 x

25

1.3 x lo5

p

C

4.1 x

25

2.9 x lo5

p

C

1.8 x

25

1.2 x lo6

/3

CONH,

A.3.1

EM"

N

H02C

CONHPh

m H02C A.3.2

c

A C O N H P h

-

-

HO,C A.3.3 HO,C L C O N H P h A.3.4 CONHPh HO,C

ANTHONY J KIRBY

232

Ref.

Amide A.3.5

PK,

kb'

T

EMa

Accuracy

c

-

7.6 x 10-6

25

5.9 x 105

p

c

-

2.3 x

25

6.6 x

lo6

p

)(/CONHPh H02C

A.3.6

CONHPh H02C

A.3.1

lo-'

c

-

8.2 x

d

-

8.2 x 10-3

25

2.0 x 10'

fi

H02CV O N H P h A.3.8

50

5x

108

y

CONHPh

HO,C

COOH-M-Sx:

Phthalamic acids

CONHR E A.3.9

C

0

2

H 3.1

R= H b

A.3.10

R = Ph

n

A.3.11

-

3.60

f

3.0

2.35 x 1.3 x 1.5 x

lo-'

2.4 x 10'

47.3 65 65.8 25

109

4x

lo9

Y

p

CONdN a

C

0

2

COOH-M-Sx: A.3.12

H Maleamic acids'

CONHMe

Rx 'C02H

CONHMe

A.3.13-16

C02H

I

4.0

6.5 x 10-5

39

2 x 109

Y

233

EFFECTIVE M O L A R l T l E S

Amide A.3.13 A.3.14 A.3.15 A.3.16

R =Me R = Et R = i-Pr R = t-Bu

EM"

39 39 39 39

6 x 10" 7 x 1010 9 x 10'" I x 1011

1.13

39

3x

3.5

3.5 x 10-2

39

I x 10'2

4.2

2.7 X 2.3 x lo-'

39 100

-

8 x 10'

Y

2.2 x 1W6 100

8 x lo3

y

?. 109

Y

PK,

I

I

3.2 3.2 3.6 3.7

l.1

4.2

I

I

1

kohl

T

Ref.

2.0 2.1 2.9 4.4

x lo-) x 10-3 x x 10-3

Accuracy y 7

y y

1013

Me

A.3.20

CONHMe

3.65

y

COOH-CN-SX

'

3.30

1.26 x lo-*

60

* EM for cyclization of succinamic acid assumed equal to that for cyclization of succinic esters

(Table A.2; see text). Direct rate comparisons give EM'S for substituted succinamic acids at 25'. No corrections for pK, Bruylants and Kezdy, 1960 Higuchi er al., 1966. Activation energy 19.5 kcal mol-I for A.3.1 Kluger and Lam, 1978. Comparison with the rate constant calculated for succinamic acid at 50' gives EM = 5 x 10'. Correction for the better leaving group uses the ratio of rates for maleamic and maleanilic acids measured by Aldersley el al. (1974b) at 39' eBender 1957; Bender e l al., 1958. EM assumed equal to the value found for cyclization of phthalate esters (Table A.2) 'In 20% dioxan (Hawkins, 1976) I Smith, 1976. Reference reaction is acetic acid catalysed hydrolysis of benzimidazole. Smith calculates EM = 8 x 104 from this comparison. Correction for the (estimated) lower pK, of the neighbouring carboxyl using /3= 1.7 (Oakenfull and Jencks, 1971) raises this to 4 x lo9 M Reference for maleamic acids is N-methylphthalamic acid, for which EM is taken as 1.0 x lo9 M (A.3.9, above) and k,,, has been measured as 4.67 x lo-' s-I at 39' (ref. i). A small

"

ANTHONY J . K I R B Y

234

correction (1.46) is also made for the slightly higher intrinsic reactivity of the benzamide [k, for N-methylbenzamide is 6.0 x loT5dm’ mol-I s-l (Bunton et al., 1972), compared with 4.12 x lo-’ dm’ mol-I s-l for N-methylacrylamide (Lancaster, 1971)l Kirby and Lancaster, 1972 Aldersley et al., 1974b Capon el al., 1978. No reference bimolecular reaction is available, but o-cyanobenzoic acid is hydrolysed over 10 times faster than phthalamic acid (A.3.9), although benzonitrile is less reactive than benzamide towards acid hydrolysis. [Rate constants for hydrolysis are (1-2) x s-l for benzonitrile in 1 M acid (Hyland and O’Connor, 1973) and 3.5 x 1C4 dm’ mol-I s-l for benzamide (Bender et al., 1958), both measured at lOO01



A.4

Lactoneformation from the cyclization of w-halogenocarboxylatees

n A.4.1 A.4.2 A.4.3 A.4.4 A.4.5 A.4.6 A.4.7 A.4.8 A.4.9 A.4.10 A.4.11 A.4.12 A.4. I 3 A.4.14 A.4.15 A.4.16

3 3 4

5 6 7 8 9 10 11 12 13 14 15 18 23

pK,

kobs

T

‘ ‘

2.86 -

‘ ‘ ‘ ‘ ‘

-

I x 10-5 2.41 x lo-] 2.6 3.1 x lo2 2.9 1.08 x 1 . 1 1 x 10-4 1.24 x 10-4 3.72 x 9.45 x 10-4 1.18 x lo-’ 3.57 x 10-1 4.65 x lo-’ 5.77 x lo-’ 5.68 x 6.70 x lo-’

45 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50

Ref.

‘ ‘ ‘ ‘ ‘ ‘ ‘



-

-

-

-

EMa 0.29 1.23 x 13.5 1.60 x 14.5 5.51 x 5.66 x 6.33 x 1.90 x 4.82 x 6.02 x 1.82 x 2.37 x 2.94 x 2.90 x 3.42 x

lo-’ 10’

lo-’

lo-‘ lo4

lo-’ lo-’

lo-’ lo-’

lo-’

lo-’

lo-’

Accuracy

B /3

a a a a a a a a a a a a a a

The reference intermolecular reaction for all the compounds listed, except A.4.1, is the S2, reaction between potassium butanoate and n-butyl bromide measured under the same conditions: 99 :1 v/v dimethyl sulphoxide-water at 50° (Galli et al., a

1973)

* Data

for chloroacetate ion in water (Smith, 1943). The reference reaction is the intermolecular esterification of the chloroacetate anion by itself ‘Galli et al., 1977. pK,-values not measured

235

EFFECTIVE MOLARlTlES

A S Intramolecular nucleophilic catalysis by the carboxyl group of the hydrolysis ofphosphate andphosphonate esters Ester

A.5.2

Ref.

CH,=C

CH,=C

2.92

lo-’

Accuracy

1.2 x

25

1.5 x 106

Y

(4.35)

3.8 x 10-3

35

(1.6 x

loJ)

Y

d

4.35

3.2 x 10-4

35

1.6 x

loJ

Y

e~f

3.15

3.44 x

lo-’

39

1.8 x 105

B

e.8

3.5

4.21 x 10-4

39

1.8 x

lo5

P

/OP\Ph

\

A.5.4

2.6 x

EM’

Y

d

4.2

T

3 x 106

‘I,,, 0 II ,OCHzPh

kob.

25

/PO(OEt),

A.5.3

PK.

CO,H

OPO(OCHzPh)2 / \

CO,H

COOH-P3-6n A.5.5 A.5.6

e.8

3.15 3.5

8.6 x 6.3 x

39 39

1.8 x 10J 1.8 x 105

P P

e.h

3.5

4.7 x 10-4

39

1.8 x 10J

B

e*f

COO--P’-6x A.5.6

nOPO(OPh),

ANTHONY J. K I R B Y

236 ~~

Ester

hf. PK.

k0bl

T

EMa

Accuracy

\

COi

COO--P'an A.5.5 A.5.6

3.15 3.5

1.38 x lo4 1.2 x lo-'

39 39

1.8 x lo' 1.8 x 10'

/3

ae**

1

3.91

2.0 x lo-'

35

3.6 x 10'

/3

k

-

1.43 x lo-'

75

2.4 x 10'

/3

39

6 x 10'

/3

a*e

/3

COo--P'-Sx

fy -PO-

A.5.9

>'

0 CH,CH(

02 - O -

COO--P'-6x A.5.10

COPh

I

,o-PO-

\O

A.5.11

I

0

4

4.0 x

EFFECTIVE M O L A R l T l E S

237

Calculation of EM. The reference intramolecular reaction is nucleophilic attack by the anion of a carboxylic acid of pK, 3.15 on 2-phenoxy-l,3,2dioxaphosphorinan-2-oxide. The rate constant for this reaction can be calculated as 7.67 x dm’ mol-’ s-’ at 39O using the formula derived by Khan and Kirby (1970), and allows the direct calculation of the EM for the corresponding intramolecular reaction (COO--P3-6n of A.5.5). The EM is assumed to be the same for the corresponding endocyclic reaction of the diphenyl ester anion (A.5.6), and has been shown not to differ significantly for endocyclic and exocyclic displacements (Bromilow el al., 1972) This now allows the calculation of EM for A.5.7 and A.5.8 using a correction factor of 10 for the decrease in reactivity expected when one “spectator” aryloxy group of a phosphate triester is replaced by an alkoxy group (Bromilow el al., 1972) The calculation for dibenzylphosphoenolpyruvate assumes that the enol dibenzyl phosphate will have the same reactivity towards bimolecular attack by RCOOH as the dialkyl phosphate group of A S S . The comparison between A.5.3 and A.5.4 shows that the substitution of an alkoxy group by phenyl increases the reactivity by an order of magnitude towards COOH, and this factor allows us to put the phosphonate A.5.1 on the scale. The intrinsic reactivity of A.5.1 and A.5.2 are assumed the same Gordon el al., 1964; Blackburn and Brown, 1969 van Holst el al., 1974 dSchray and Benkovic, 1971. The pK, and EM for A.5.3 are assumed to be the same as for A.5.4. The rate constants are not corrected for exocyclic vs. endocyclic displacement Bromilow el al., 1972 ’Corrected for 20% endocyclic displacement Corrected for 13% endocyclic displacement * Corrected for 96% endocyclic displacement Simons, 1974 ’Steffans el al., 1973, 1975. The reference reaction is the attack of the anion of a carboxylic acid of pK, 3.91 on methyl 2,4-dinitrophenyl phosphate at 39O (Kirby and Younas, 1970). The intramolecular reaction is corrected for the better leaving group using ,3,/ = 1.26 (Khan el al., 1970), and to 39O using the activation energy measured for the intermolecular reaction with acetate (Kirby and Younas, 1970). ‘Steffens el al., 1975. The rate of the same reference reaction (note/? was extrapolated from 60° to 75O using an activation energy of 22 kcal mol-I (Kirby and Younas, 1970), and the same correction for leaving group applied as inj. The pK, of the substrate carboxyl group was estimated to be 4.4 ‘Khan el al., 1970. The intramolecular and reference reactions are now at the same temperature, and the leaving group correction is applied in the series for which BL0 was measured (note 57. The major remaining uncertainty concerns the comparison of an intramolecular reaction of a diary1 phosphate with an intermolecular reaction of a methyl aryl phosphate. This is not a large factor; the second order rate constant for the reaction of pyridine with bis-2,4-dinitrophenyI phosphate is less than three times greater than for the same reaction with methyl 2,4dinitrophenyl phosphate (Kirby and Younas, 1970). For the 2-carboxylatophenyl group a factor of two is a good estimate a

ANTHONY J. KIRBY

238

A.6 Intramolecular nucleophilic catalysis by the carboxyl group of the hydrolysis of sulphonamides"

Ref.

PK,

k0b*

T

EMb

Accuracy

C00H4-4~ A.6.1 A.6.2

2.49 2.78

2.26 x 1.74 x

75 75

4 x lo6 8 x 10'

Y Y

d

3.44 -

5.32 x 10-4 4.5 x 10-3

75 75

-

c

2 x 107

Y Y

2.5 x lo-'

75

3x

lo6

Y

HO,CCH,SO,NMePh HO,CCMe,SO,NMePh COOH-S-SX

A.6.3

HO,C(CH,),SO,NMePh

A.6.4

3.67

A.6.5

3.63

1.29 x

lo-)

75

3 x lo6

Y

3.64

1.62 x 10-3

75

2 x 103

Y

2.01

2.78 x

75

-

Y

1.0 x 10-2

75

4 x 10'0

Y

4.79 x lo-) 8.0 x

75 75

1 x 10'

Y Y

Y

A.6.6

I-!:

d

aCO,H A.6.7

(,02NMeph C02H A.6.8

A.6.9

c

-

2.67

aI;e'"

c

S0,NMePh

-

lo-'

2.51

7.2 x

lo-'

75

3 x 10)

3.90

1.3 x

lo-*

75

2 x lo3

Y

4.88

3.3 x

75

6 x 10'

Y

CO,H COOH-S--6~ A.6.10 A.6.1 I

HO,C(CH,),SO,NMePh SO,NMe,

E F FECTl VE M 0 LAR IT1ES

239

Data are from Graafland et al., 1979 No intermolecular counterpart to this reaction is available. The EM's are assumed to be the same for compound A.6.4 and A.6.5 as for the corresponding phosphonate ester (A.5.1), which involves a similar mechanism and almost identical geometry. EM's for other sulphonamides are then calculated by direct rate comparison with A.6.4 or A.6.5 after correction for the difference in pK.. The correction is based on /3= 0.72 for the COOH group, calculated from the measured pcooH = -0.54 for the hydrolysis of ring-substituted derivatives of A.6.5 and p = 0.75 2 0.05 for the pK,-values of the same compounds (Graafland et al., 1979) Measured in 50% aqueous ethanol In water a

B

REACTIONS OF T H E H Y D R O X Y L G R O U P

B. 1 Equilibrium constantsfor the lactonization of hydroxy acids

Hydroxy acid B.l.l B. 1.2

rn

yHydroxybutyric

HO

B.1.3

0 ,,+

B.1.5

B.1.6

T

EM"

Accuracy

e

6.15 11.13

25 25

88 159

P P

28 10

25

4 x 104

P

25

1.8 x 105

P

30

1.6 x 10'

P

C

C

Co2H CH,OH

.Pi

HO

Kb

CO,H

"o,,

6.1.4

Ref.

1.27 x lo'

CO,H

0.621 *02H

\

240

A N T H O N Y J KIRBY

Hydroxy acid

Ref.

Kb

T

EM"

Accuracy

d

>99

30

>2.6 x 107

B

30

3.7 x 10"

/?

30

2.0 x 1013

p

1.42 x

f

lo6

7.51 x 107

,,Reference reaction is the formation of ethyl acetate from ethanol and acetic acid at 25O (Gerstein and Jencks, 1964) Data at 25O in 2096 ethanol-water Storm and Koshland, 1972a Milstien and Cohen, 1972. Reference reaction is the formation of phenyl acetate from phenol and acetic acid at 25 O in water Hershfield and Schmir, 1973a For reference reaction, see note d 'Hershfield and Schmir, 1973b.For reference reaction, see note d

24 1

EFFECTIVE MOLAR IT1E S

B.2

Acid-catalysed Iactonization of hydroxy acids kob;

T

EM”

4.72 1.43 x lo-’ - 2.12 x 10-3 5.09 0.12 5.44 18.7

25 25 25 25

80 117 6.62 x lo3 1.03 x lo6

a

d

-

25

6.5 x lo4

a

d

-

d

-

1.78

25

9.8 x lo4

a

B.2.8

d

-

2.53

25

1.4 x 13’

a

B.2.9

C

-

-

25 45 25

9 x 104 -

p

C

45

1.4 x lo6

p

Hydroxy acid HO-A-5x:

B.2.1 B.2.2 B.2.3 B.2.4

Ref.

c C C

e

B.2.5

1.58 x lo-’

25

87 1

a

CO,H

f

B.2.10

a

CO,H

B.2.7

HO

1.18

a

a

CO,H

B.2.6

HO

Accuracy

pHydroxy acids

B.l.l B.1.2 B.1.3 B.1.4

HO

pK,

e

-

5.73 x 10-3 2.25 x lo-, 4.88 x lo-’ 0.349

242

p:H Hydroxy acid

B.2.11

B.2.13

Ref. e

pK,

-

q:H

ANTHONY J. K I R B Y

kobt

T

EM"

1.19

45

5 x 106

Accuracy

p

13.3

25

2.5 x 10'

B

-

48

25

109

Y

-

h

I

-

8

8

Me Ph

B.2.14

Me Me

B.2.15

33.9

3 x 10'

y

8

15.5

3 x 10'

y

250

15.5

10'O

Y

Ph Ph

B.2.16 H:&

B.2.17

K

B.2.18

Me Me

o

H

H

J,k

-

1.1

-

EFFECTIVE M O L A R l T l E S

2 43

Ref.

Hydroxy acid

pK,

kobsb

T

EM"

5.9 x lo-'

30

4.0 x 10'

7.0 x lo-'

30

4.7 x 10.'

4 x 10-5

30

2.7 x lo5

Accuracy

~

SHydroxy acids

HO-A-6x:

B.2.19

B.2.20

3.2 x 106

B.2.21

2.6 x lo-.

30

1.7 x 10'

2.8 x

30

1.9 x 10'

B.2.22

9.85 x

30

6.6 x lo8

B.2.23

(5.0 x 10')

30

26.2

30

B.2.24

(1.5 x lo6)

B.2.25

(2.0 x lo6)

q

B.2.26

C

0

.

H

i~

1.7 x 10"

Y

5 x 10"

Y

30

30

-

7 x 10"

1.18 x 10-3

30

8.0 x lo6

244

A N T H O N Y J. KIRBY

Hydroxy acid

Ref.

pK,

kob;

T

EMa

Accuracy

30

5.2 x 10'

B

30

6.9 x [email protected]

B

B.2.27

B.2.28

3.7

B.2.29

3.25

P

B.2.30

z

0.103

H

bozH \

B.2.3 1

O

7.78 x

3.84 6.82 x

30

4.5 x 10'

B

4.50 3.75 x

30

2.5 x 10'

p

/

The reference intermolecular reaction for the aliphatic compounds is the formation of ethyl acetate from ethanol and acetic acid measured under the same conditions (20% ethanolwater, ionic strength 0.4 M) by Storm and Koshland (1972a). The esterification of benzoic acid in methanol at 25' is 290 times slower than that of acetic acid (Kirby, 1972), so this factor is used to correct the EM'S, calculated otherwise in the same way, for the hydroxybenzoic acids. For the phenolic acids see notes rn and n Rate constants are in units of dm' mol-I s-' Storm and Koshland, 1972a ,I Storm and Koshland, 1972b Bunnett and Hauser, 1965 'Chiong er al., 1975; in water containing 3.2% ethanol 'Weeks and Creary, 1970. Estimated from observed rate constant of 8.37 x lo-' s-' at 33.9', pH 3, for B.2.14. The measured rate constant at 20' is 33.3 dm' mol-I s-' (Milstien and Cohen, 1972) 2.9 times slower than B.2.14, above . Probably faster than compound B.2.25 (Hillery and Cohen, 1972) Kirby and McDonald, unpublished a

EFFECTIVE M O L A R l T l E S

245

33 times less reactive than B.2.18 at pH 3.25 'Calculated from k,,, = 0.14 SKI at pH 3.25, using A H t = 15 kcal mol-' In 20% dioxan-water (Milstien and Cohen, 1972). The reference reaction is the formation of phenyl acetate from phenol and acetic acid at 25O (rate constant estimated at 1.5 x dm' mol-' s-l). These authors' very high rate constants for the lactonization of compounds B.2.23-25 (data in parentheses) which lead to much quoted EM'S in the region of 10l6M, appear to be too high by several orders of magnitude (Caswell and Schmir, 1980) " In 20% dioxan-water (Caswell and Schmir, 1980). Reference reaction as in note m 'EM from direct rate comparison with B.2.19, using Milstien and Cohen's data EM from direct rate comparison with B.2.23, using Milstien and Cohen's data q Measured under the same conditions as B.2.19-25 Danforth ef al., 1976. For reference reaction see note m Hershfield and Schmir, 1973a. For reference reaction see note m Hershfield and Schmir, 1973b. For reference reaction see note m B.3

Base cafalysed lacfonization of hydroxy esters

Ester

Ref.

PK,

k0bl

T

EM

Accuracy

3.5 x lo8

B

280

P

O---E-Sx

B.3.1

B.3.2

B.3.3

B.3.4

9.0

Me

2.23

25

C0,Ph

0-

c

0--E-6~

B.3.5

C0,Ph

0-

*** (15.9)

f

29.8

246

ANTHONY J. K I R B Y

Ref'

Ester

PKa

kobs

(10.0)

8

T 25

EM"

Accuracy

5 x 10'

3/

C0,Ar

0Capon er al., 1973 bThe pK,-value is estimated in order to allow the calculation of the first order rate constant for cyclization of the anion from k,,, and the reference reaction is the attack of methoxide ion on phenyl acetate (Bender and Glasson, 1959) cThe pK,-value is estimated. The reference reaction is the attack of phenolate anion on phenyl acetate (Bender and Glasson, 1959) dFife and Benjamin, 1973. The reference reaction is attack by alkoxide on ethyl benzoate estimated from the known second order rate constant for attack by hydroxide in water at 25O (Bender, 1951) and allowing a factor of 10 for the higher reactivity of aIkoxides (Gilchrist and Jencks, 1960). The pK,-value is taken as that of benzyl alcohol (Takahashi et al., 197 1) Hutchins and Fife, 1973. The reference reaction is the attack of the anion of a phenol of pK, 9.0 on phenyl N-methyl-N-phenylcarbamate under the same conditions f 18 times slower than B.3.1 'Ar = 2-naphthyl. This ester is about 5 times less reactive than 2-naphthyl 2-hydroxyphenylacetate in 20% dioxan-water

B.4

Epoxide formation from chlorohydrins Compound

Ref.

pK,

kObS(I

T

EMb

14.31

2 x lo-,

25

2.5 x lo3

y

Accuracy

0--C-3~ B.4.1

-cl

c

0-

1.05 x lo-' 18

B.4.2

13.64

0.24

25

3 x 104

y

B.4.3

dre

15.5

3.42

18

8 x 10'

y

B.4.4

d.e

14.5

9 x lo-'

18

2 x lo4

y

B.4.5

d.e

16.5

410

18

108

Y

EFFECTIVE MOLARlTlES

247

Ref

PK,

kobsD

T

d.e

14.5

4.1

18

B.4.7

d. e

16.7

3.5 x 103

18

B.4.8

d. e

15.7

530

18

16.7

3.0 x 104

18

Compound -

B.4.6

0i-X"'

B.4.9

EMb

Accuracy

Rate constants are calculated from the observed second order rate constant for hydroxidecatalysed cyclization and the pK, given Effective rnolarities are based on the calculation for the formation of oxetane (see reaction B.5.1) and are derived by direct rate comparisons Knipe, 1973 Data of Nilsson and Smith, 1933 pK, estimated by the method of Takahashi et al. (197 1) 'There is no satisfactory intermolecular counterpart to these reactions. No corrections have been made for the effects of the methyl substituents in these compounds

B.5 Base-catalysedformation of cyclic ethers

Alcohol

Ref.

pK,

kobt

T

EM

Accuracy

~

0--C-4~ b*c

b*c*d

15.23 3.74 x

30

4

P

16.5

30

1700

P

8

P

1.58 x

A N T H O N Y J. KIRBY

248

Alcohol

Ref.

pK,

kobaa

T

EM

Accuracy

15.56

0.104

30

6 x lo'

y

7

25

390

B

30

280

Y

O--C-~X

B.5.4

HO(CH3,CI

O--C--6x b.c*d

15.70

5.0 x

249

EFFECTIVE M O L A R l T l E S

Alcohol

Ref.

pK,

kesa

T

EM

Accuracy

-

1.92

50

6560

a

-

1.55

50

3880

a

I

1.1

0- Br

B.5.14

m

-

0.237

30

6.6 x

lo3

/I

m

-

1.65

30

4.6 x l(r

/I

736

30

2.0 x 10'

/I

30

5.7 x

B.5.15

m

B.5.17

m

-

-

2.05 x

loJ

lo9

/I

250

ANTHONY J. KIRBY

Alcohol

cyclization of

Ref.

kObP

pK,

uo[a1

B.5. I8 B.5.19

[a], n = 7 [bl, n = 7

I

B.5.20 B.5.21

[a], n = 8 [bl, n = 8

I

B.5.22 B.5.23

J

B.5.26 B.5.27

[a], n = 9 [bl, n = 9 [a], n = 10 [bl, n = 10 [a], n = 11 [bl, n = 11

B.5.28 B.5.29

[bl, n = 12 [b], n = 13

1

B.5.30 B.5.31

[a], n = 14 [bl, n = 14 [a], n = 16 [bl, n = 16 [bl, n = 24

J

B.5.24 B.5.25

B.5.32 B.5.33 B.5.34

T

EM

Accuracy

a a a a a a a a a a a a

[bl

3.45 x 1.45 x lo-*

50 50

118 36.3

1.03 x lo-‘ 6.61 x lo-‘

50 50

0.352 1.66

1.63 x lo-’ 1.23 x lo-‘

50 50

5.57 x 0.308

1.46 x lo-’ 6.07 x

50 50

4.99 x lo-* 0.152

I

3.96 x

I

1.85 x lo-’

50 50

4.64 x

2.27 x lo-’ 1.50 x lo-’

50 50

5.69 x 3.76 x

3.35 x 8.89 x

50 50

1.14 x 2.23 x

4.75 x 9.07 x 2.56 x lo-’

50 50 50

1.62 x 2.28 x 6.42 x

1

1

I

I 1

I

1

J I 1

1.35 x

a a a a

a

“Rate constants calculated from the observed second order rate constant for hydroxidecatalysed cyclization, and the pK,-value given bEM’s based on the observed product ratio for the base-catalysed cyclization of 3-chloropropanol in 40% methanol-water (Richardson et al., 1971). Over a range of temperatures the amounts of cyclic ether (14%) and 3-methoxypropanol(50%) were constant within experimental error. From the known molarity of methanol in the solvent the EM of the neighbouring group is readily calculated as 2.77 M, and a small correction for the difference in pK, between 3-chloropropanol (15.23) and methanol (15.09) gives a value of 3.82 M for the EM of the 0group of 3-chloropropoxide relative to intermolecular attack by methoxide In 40% methanol-water (Richardson et al., 1971) Rates at 30° extrapolated from Arrhenius parameters given. pK, estimated using linear free energy relationship given by Takahashi et al. (1971) Richardson et al., 1971. EM based on comparison with the reaction of 3-chloropropanol under the same conditions, corrected for change of solvent from the figure given in B.5.1 (kobs= 6.8 x dm3 mol-’ s-l in water) on the basis of the results of Stevens et nl. (1948) [Compare 8.1 x lo4 M calculated independently by Page (1973)l ’Coward et al., 1976

25 1

EFFECTIVE MOLARlTlES

The EM refers to the pH-independent reaction which is compared to the attack of water on the dimethyl p-nitrophenyl sulphonium cation Irie and Tanida, 1979 'Capon and Thornson, 1977. The reference reaction is attack by phenolate anion on an epoxide "of this type" 'Illuminati et al., 1974, 1975, 1977. The reference intermolecular reaction is the alkylation of o-ethylphenolate anion by n-butyl bromide under the same conditions. Reactions were run using the fully ionized substrate in 75% ethanol-water kBeU el al., 1974. The reference intermolecular reaction is of the anion of p-hydroxyacetophenone with EtCOCH,Br under the same conditions As for note j except that the reference reaction is alkylation of the guaiacol anion '"Borchardt and Cohen, 1972. EM's based on relative rates assuming equal EM's for the bromide and mesylate, B.5.10 and B.5.12 8

'

B.6

Intramolecular cyclization of hydroxyalkyl phosphates Ester

Ref.

pK,

k,,,,,"

T

EM

Accuracy

25

1 x 10'

y

B.6.1

15

B.6.2

330

O--P'-Sx B.6.3

B.6.4

B.6.5

C.d

14

1.4 x

100

1.3 x lo4

y

15

2.6 x

100

2.5

lo4

y

8.5 x

100

8 x lo4

y

xo'po/oR c,d

0-

15

X

2 52

A N T H O N Y J. KIRBY

Ester B.6.6

Ref

14

,OR

,OPh

kob,"

T

3.7 x lo-'

100

6.0

50

PK,

13.92

EM 3.6

X

Accuracy

lo6

y

3 x 107

0For intramolecular reaction of anion Gay and Hamer, 1970. The reference intermolecular reaction is the attack of hydroxide on the methyl ether of B.6.1, corrected (factor of 10) for the expected higher reactivity of an alkoxide anion eBrown and Usher, 1965a. R = cyclohexyl. The EM'S are calculated by comparison of data for one phenyl ester (B.6.4; R = Ph; Brown and Usher, 1965b), extrapolated to 2S0, with the intermolecular attack of hydroxide on diphenyl phosphate (k,= 1.56 x lo-' dm' mol-I s-l at 25O; Kaiser and Kudo, 1967). Hydroxide deviates little from the Brmsted plot for a series of oxyanion nucleophiles attacking methyl 2,4-dinitrophenyl phosphate, so the only correction made is a factor of 2 for the increased reactivity of a diary1 phosphate compared with an alkyl aryl phosphate anion. The EM can thus be calculated directly for B.6.4 (assumed not to change with the leaving group) and B.6.7, and for the other cyclohexyl esters by rate comparisons with B.6.4 pK,-Values estimated by the method of Takahashi et al. (197 1) Usher et al., 1970

c

REACTIONS OF T H E S U L P H Y D R Y L G R O U P

C. 1 Equilibrium constants for thiolactoneformationfrom y-thiolacids

HS Acid C. 1.1

s-co

CO,H Ref.

y-Thiolbutyric

c.1.2

SH

Ka

T

EMb

Accuracy

2.44

25

3.7 x 10'

P

1.10

25

1.7 x 10'

P

2 53

EFFECTIVE M O L A R l T l E S

4cozH Acid

C.1.3

K"

Ref.

63

T

EMb

Accuracy

25

9.5 x 104

P

SH

C.1.4

" Determined in 0.1 M HCI

The reference reaction is the formation of ethyl thiolacetate from ethanethiol and acetic acid (Gerstein and Jencks, 1964) Storm and Koshland, 1972b C.2

Thiolactonization of y-thiol-acids. etc.

Acid

pK,

Ref.

kob;

T

EMb

2.05 x 4.80 x 2.50 x lo-' 4.38 x

25 25 25 25

384 90 4700 8.21 x loJ

24

25

1.6 x 10'

Accuracy

HS-A-SX c.2.1 c.2.2 C.2.3 C.2.4

4.80 5.42 5.06

c.1.1 c.1.2 C.1.3 C.1.4

b*e b*e

U U

a

u

C.2.5

S--E-Sx C.2.6

Me

8.7

d

" Acid-catalysed reaction measured in the range pH 1-4. Units dm'

a

mol-I s-l The reference intermolecular reaction is the esterification of acetic acid by ethanethiol under the same conditionse Storm and Koshland, 1972b dFife ef al., 1975. The reference reaction is attack by 2-arninoethanethiolate anion @K, 8.3) on p-nitrophenyl N-methyl-N-phenylcarbamate,corrected to pK 8.7

ANTHONY J. KIRBY

254

D

REACTIONS OQ THE AMINO-GROUP

D. la Intramolecular attack by the dialkylamino-group on a neighbouring ester group

Solvent

k,","

k,",,,

N-E-4n

D.1.1'

Et,N,?S,

+u7

Et,N-CH,-S-

I

Ac Nitromethane Acetonitrile Chloroform Acetone MeOCH,CH,OMe n-Hexane

a

-

T

EM

Et,NAc

+ (CH,S),

1.44 x 3.06 x 6.39 x lo-' 2.72 x 1.36 x 1.94 x lo-'

5.0 x lo-' 1.39 x lo-' 1.72 x 3.33 x 1.36 x 6.94 x lo-'

27 27 50 50 50 50

0.029 22 0.037 0.8 1.o 0.28

0.17 0.55 9.7 358

-

20 20 20 20

1260 1080 1700 5400

6.5 x lo-, 0.33 4.25 167

-

20 20 20 20

490 650 750 2330

Accuracy

B

P B B P B

N-E-SX

a

a

a a

N-E-~x

D.1.6' D.1.7' D.1.8' D.1.9'

Ar = Ph Ar =p-CIC6H4 Ar = m-NO,C,H, Ar =p-NO,C,H,

a a

a a

Both intermolecular and intramolecular reactions can be measured for this reaction. EM is calculated as the ratio of the rate constants for the intramolecular (s-l) and intermolecular reactions (dm' mol-I s-l). Data of Searles and Nukina, 1965 'Bruice and Benkovic, 1963. The reference reaction is the attack of trimethylamine on the corresponding aryl acetate under the same conditions a

255

EFFECTIVE MOLARlTlES

D.1b Intramolecular nucleophilic attack by imidazole and pyridine Ester

Ref.

PK,

kobs

T

EM

Accuracy

6.91 6.69 6.79 6.24

4.3 x lo-, 0.17 2.4 33.3

25 25 25 25

-

73

P

7.55

8.8 x

lo-,

30

53

B

N-E-~x

4

H N ,N:-0Ar

D.l.10 D.1.1 1 D.1.12 D.1.13

Ar=Ph Ar = p-CIC,H, Ar = m-NO,C,H, Ar =p-NO,C,H,

(I

O

a O

D.1.14

N-E-ttt~

D.1.1SE

CH,NH(COCH,NMe),COCH~CH,CO#NP I

25

For m = 25-100 EM falls from

2.5 x lo-,

- 4 x 10-3

to

D.1.16d

CH,CH,O(CH,CH,O),COCH~CH,CO~NP I

EM is maximum near m = 32-33 (n = 7) EMfdsoffasm+100to

25

-6 x lo-’ -2 x lo-’

a

4Bruice and Sturtevant, 1959. The EM’S are complicated by a mechanism change for the substituted compounds (see footnote b) and are based on the reaction of the phenyl acetate with imidazole Bruice, 1959 Sisido et al., 1976.Reference reaction is of the substrate with pyridine Sisido et al., 1978.Reference reaction is of the substrate with pyridine

ANTHONY J. KIRBY

256

D.2 Intramolecular nucleophilic attack by the NH, group Ref.

pK,

T

kobs

EM

Accuracy

Fife et al., 1975. The EM is based on an estimated lower limit for the rate of the reaction of cyclohexylamine with p-nitrophenyl N-methyl-N-phenylcarbamate(aniline does not react at all) and requires a long extrapolation from pK, 10.7 to 2.7, using /3 = 0.8 (I

D.3

The cyclization of halogeno-amines, ere. Amine

PK,

Ref'

k b s

T

EMa

Accuracy

N-C--3~

D.3.1

8.8c 1.74 x

25

15

Y

D.3.2

8.65

5.6 x lo-'

25

15

Y

8.97

8.0 x

75

15

Y

-0s0,

D.3.3 HZN

D.3.4 D.3.5 D.3.6

'

MeZNl-' Me,N

mBr

Et,N -cl

d

d*g

D.3.7 Me2N/Yc1

2.88 x lo-'

25

1.3

Y

10-2

25

-

Y

8.80

9.33 x lo-'

25

2000

Y

8.31

1.62 x lo-'

25

9

Y

8.2 -

D.3.8

d*h

8.9

2.0 x

25

D.3.9

d*h

8.6

7.9 x

25

6

Y

25

30

Y

D.3.10

7.6

1.81 x lo-'

1.5

Y

EFFECTIVE M OLARl TI E S

257

-

b~J

3.29 x 10"

25

1

15

N-C--4~ D.3.14 D.3.15 D.3.16

H,N(CH,),Br Me,N(CH,),CI H,N(CH,),OSO,

m

-

8.3 x lo-, 1.08 x lo4 9.08 6.5 x lo-'

25 56 75

0.2

-

Y

0.2

Y

9=

N-C-SX D.3.17 D.3.18

H2N(CH2),Br H2N(CH2),CI

9 3 -0.5 9.58 5.84 x lo-'

25 25

7000 3000

Y Y

D.3.19

Ph

8.45 5.44 x lo-)

25

6000

Y

3.57 2.74 x 10-3 10.28 3.55 x lo-'

2s 75

3000 3000

I

25 73 73 73 73 73 73

100 100 1.7 2 x lo-, 9 x 10-2 4 x lo-' 0.15

0 D.3.20 D.3.21

-

C

I

PhNH(CH,),CI H,N(CH,),OSO,

b

Y

N-C-(616)x D.3.22

H,N(CH,),Br

9.8c n

D.3.23 D.3.24 D.3.25 D.3.26 D.3.27

H,N(CH,),Br H,N(CH,),,Br H,N(CH,),,Br H2N(CH2),,Br H,N(CH,),,Br

-

10.w

n n

-

n

-

R

-

n

-

8.3 x 3.3 x 5.5 x 6.7 x 1.2 x

lo-' 10-2

10-4 lo-, 10-5 1.3 x lo-' 2.5 x lo-'

Y

B B B B B

A N T H O N Y J. K I R B Y

258

Amine D.3.28

Me

I

Ref. 0

PK, -

koba

1.2 x 10-3

T

EM4

Accuracy

25

3 x 10-3

u

'The reference reaction is the S,2 reaction of the closest amine (trimethylamine, triethylamine for dimethyl and diethylamino-compounds, ethylamine for the primary amines) with the chloroacetate anion in water at 25O [data of Moore el al. (1912)l. The reference reactions are not expected to involve participation by the COO- group (Gacek and Undheim, 1973), but may underestimate rate constants for an ideal intermolecular reaction because of the aniondipole interaction, thus overestimating EM. Page's value of EM = 1.4 x 10' for D.3.17 is actually based on data for the reaction of Et3N with EtI, not EtBr, with both temperature and solvent extrapolations (Page, 1973). Where an independent estimate of EM is possible (D.3.22) the value calculated by the above method is in agreement (see note n). The data are corrected for pK, differences, using = 0.27 (Dixon and Bruice, 1971) In 50% dioxan-water (Bird ef al., 1973) =The value of pK, is estimated from the linear free energy relationship given by Takahashi et al. (197 1) Hansen, 1962,1963a Dewey and Bafford, 1967. EM is assumed for D.3.3 which is used to calculate EM'S for D.3.16 'Simonetta er al., 1950 'Et,N reacts with chloroacetate almost 80 times more slowly than does Me3N yet the intramolecular reaction of the diethylamino-compound is 32 times faster than that of D.3.5. Most of the difference in EM is therefore probably real * Reference reaction is of Me3N, since the ring N shows much less steric hindrance than Et3N pK, is based on that of D.3.19 and standard effect of b-Cl 'EM'S are assumed the same as D.3.1-3 and D.3.18 respectively. These are certainly underestimates, but by how far is difficult to say 'Hutchins and Rua, 1975. Based on Me,N(CH,),CI (D.3.4); rate constant 6.22 x lo-' s-l at Oo, and EM = 1.3 M Freundlich and Kroepelin, 1926 In 80% ethanol (Grob, 1969); safe extrapolation to aqueous solution at 25O is not possible "Data of Salomon (1936) at 73.35O in 30% aqueous isopropyl alcohol. No pK,-values are available. The EMS quoted are derived independently of those above from comparison of the rates of the intramolecular and intermolecular reactions of these compounds [the so-called cyclization constants of Stoll and Rouve (1934) referred to on page I881 In dioxan (Lok and Coward, 1976). The reference intermolecular reaction is demethylation by piperidine under the same conditions

'

2 59

EFFECTIVE MOLARlTlES

D.4

Intramolecular nucleophilic attack on phosphorus Ester

-

PK,

kobs

T

EM

Accuracy

4.2

3.5 x 10-4

60

1.1 x 103

fi

b

9.4

2.7 x 10-3

35

1.5 x lo6

p

C

-1

>2 x 10-2

22

> 109

Y

Ref.

N-P'--Sx

D.4.1

\ o,

-0,p

GOpNP

D.4.2 EtNH

POT-OpNP

D.4.3 r " v pQ OA 'O ' Ph

-

Loran and Williams, 1977. The reference intermolecular reaction is the attack of pyridine on methyl o-nitrophenyl phosphate (Kirby and Younas, 1970). Corrections for the conversion to a diary1 ester and a p-nitrophenyl leaving group are assumed to cancel out. Temperature correction uses E, = 14.8 kcal mol-', as measured for the reference reaction Lazarus et al., 1980 CRiley et al., 1957. Reference reaction is nucleophilic attack of ethyl glycine on methyl 2,4-dinitrophenyl phosphate (Kirby and Younas, 1970), corrected for the leaving group using ,3,/ = 1.0 and for pK of the nucleophile using B = 0.3 1 a

I1 INTRAMOLECULAR GENERAL BASE CATALYSIS E

CATALYSIS B Y THE IONIZED CARBOXYL GROUP (TABLES E-G)

E. 1 Intramolecular general base catalysis of ester hydrolysif' Ester ~~~

Ref.

PK,

kobs

T

EM

Accuracy

~

COO-(HO)E-qx

0-3H-0

/H

OAr E.l.l

Ph02CCH2CO;

3.15

1.43 x

39.6

25

a

260

E.1.2 E.1.3

ANTHONY J. K I R B Y

Ester

Ref.

PK,

kb.

T

EM

Accuracy

PhO,CCMe,CO, ArO,CCEt,COr

b*c

3.11 3.2 3.2

6.67 x 2.90 x 3.48 x lo-'

39.6 39.6 39.6

11 0.3 60

a a

3.03

1.33 x lod

80

24

a

3.39

7.42 x lo-, 7.43 x lo-*

25 25

15 -

a

6.69 x

25

13

a

b*c b~C

E.1.5

PhCO,CH,CO,

dpc

0

C OO-(HO)E--74n

II

h

E'1*7

~

~

~

C

a

H

C

-

l

@

,

3.52

EFFECTIVE MOLAR IT1ES

Ester E.l.10

a

C

O

7

261

Ref.

PK,

kohl

T

EM

8

3.70

9.06 x lo-,

25

18

3.42

6.65 x lo-'

25

Accuracy a

OCOCHCI, E.l.ll

P

C

O

i

1.4

a

OCOCHCI,

E.1.12 E.1.13

X=OMe X = NHCONH,

'

3.38 3.38

25 25

1 23

P P

For notation see pages 191-2 Kirby and Lloyd, 1976b; Ar(E.1.3) =p-nitrophenyl CThe reference intermolecular reaction is general base catalysis of the hydrolysis of phenyl acetate by the anion of a carboxylic acid of pK, 3.1 Arcelli and Concilio, 1977 The reference intermolecular reaction is the observed general base catalysis of the hydrolysis of the substrate by external carboxylate 'Fersht and Kirby, 1967b 'Gandour el al., 1979. The reference reaction is general base catalysis of the hydrolysis of phenyl dichloroacetate at 25O by external carboxylate of the given pK,. Rate constants calculated from a two point Brensted plot using the data of Fersht and Kirby (1967) Minor and Schowen, 1973 St. Pierre and Jencks, 1968. The reference intermolecular reaction is the carboxylate-catalysed aminolysis of phenyl acetate, corrected for the pK, of the general base

262

ANTHONY J K I R B Y

E.2 Intramolecular general base catalysis of S c h i r s base hydrolysisa

k,,,

T

E.2.1

3.68 x lo-*

25

30

E.2.2

2.0 x 10-3

25

1

3.20 x lo-*

25

31

PK.b

Compound

EM' Accuracy

coo-(so,c=~-~", 7f.

E.2.3

2.09, 3.86

0 Kayser and Pollack, 1977 pK,-Values estimated by authors Reference intermolecular reaction is external general base catalysis by the anion of a carboxylic acid of the same pK,

E.3 Intramolecular general base catalysis of enolization Ketoacid

E.3.1 E.3.2 E.3.3

CH,COCH,CH,CO,H C H,COCH2CHMeC02H CH3COCH2CMe2CO2H

Ref.

bre

'x b-e

PK,

4.61 4.57 4.69

kobs

3 x lo-' 5 x lo-* 7 x lo-'

T

25 25 25

EM" Accuracy

0.1 0.1 0.3

P a

EFFECTIVE M O L A R IT1ES

263

Ketoacid

4.72 4.67

1.05 x lo-' 8.4 x lo-'

25 25

EM" Accuracy a 0.5 a 2.3

b.c

4.73 4.77

1.80 x 1.30 x lo-'

25 25

9 50

P

b*c

4.73 4.83

8.3 x lo-' 9.0 x lo-'

25 25

0.5 4.5

a a

4.61 4.57 4.69 4.58

2.5 x lo-' 2.6 x lo-' 5 x lo-" 1.87 x lo-'

25 25 25 25

0.9 0.7 0.2 1.0

a a a a

Ref.

PK,

kobs

T

~

E.3.4 E.3.5

Bu'COCH~H,CO,H PhCOCHFH,CO,H

brc

COO--H-qx

C O

0 E.3.6 E.3.7

CHlCOCH2(CH,),C0,H PhCOCHz(CHJ2CO2H

b*c

a

COO--H-6fx E.3.8 E.3.9

CHlCOCH~CH2)lC02H PhCOCH2(CH,)lC0,H COO--H-6fn

E.3.10 E.3.11 E.3.12 E.3.13

C H K 0(CH ,),C 0,H CHKOCH,CHMeCO,H CHXOC H,CMe,CO,H CHKOCMe,CH,CO,H

b*c b-c

b,c

E.3.14

Y

0 E.3.15

q?

'*d

3.45

cad

3.65

3.3 x lo-'

25

2.6

P

25

>20'

y

CO,H

E.3.16

0

2.65 x

ANTHONY J. K I R B Y

264

Ketoacid

E.3.18

0

Ref.

c,d

f

PH,

3.68

T

kobs

5.02 x

25

5 x

25

EM“ Accuracy

>2oC 56‘

a

p

The reference intermolecular reaction is general base catalysis of the enolization of the substrate by external acetate Bell and Covington, 1975 pK,-Values given are the “true” pK, calculated from rate constants for nitramide decomposition where necessary. Observed pK,-values are complicated by lactol formation Bell el al., 1976 For these more efficient reactions the rate of the intermolecular reaction (acetate-catalysed detritiation) is too slow relative to that of the intramolecular reaction to be measured accurately. These EM’S are therefore based on estimated upper limits for the rates of the reference reactions f Harper and Bender, 1965. The reference intermolecular reaction is the benzoate-catalysed enolization of PhCOCHMe,

F

INTRAMOLECULAR G E N E R A L B A S E CATALYSIS BY PHENOLATE OXYGEN

F. 1 Catalysis of ester hydrolysis Ester 0-(HO)E-qx

Ref.

PK,

kobs

T

EM Accuracy

EFFECTIVE MOLARlTlES

Ester

265

Ref.

PK,

kobs

T

EM Accuracy

Capon and Ghosh, 1966. No appropriate reference intermolecular reaction rate has been measured for an aryl benzoate. The reference used is the intramolecular general base-catalysed hydrolysis of salicyl salicylate (Kemp and Thibault, 1969) which has khvd= 2.89 x s-l in water at 30°. If the EM is assumed to be the same as for aspirin (13 M) this corresponds to an intermolecular reaction of an aryl benzoate catalysed by benzoate with k, = 2.22 x lo-’ dm’ mol-l s-l. The correction from the pK-value of salicyl salicylate (3.6) to the pK, of the substrate uses 8=0.5 (cf. 0.52 for the aspirin reaction). The temperature sensitivity is also taken to be equal to that of the aspirin reaction bHansen, 1963b, c. The reference intermolecular reaction is calculated, in the way described in note a from data for aspirin a

F.2

Catalysis of enolization

Ester

Ref.

PK,

kobs

10.27 2.4 x lo-’

T

EM

Accuracy

25

(1.3), 14c

y

Bell and Earls, 1976. The reference intermolecular reaction is that of the substrate with itself Bell el al., 1976 CThe reference intermolecular reaction is that of a base of pK, 8.05 (reckoned to be the appropriate figure for the non-H-bonded OH of an o-hydroacetophenone) and either the substrate (1.3 M, which underestimates k, because it is negatively charged) or acetophenone, which may overestimate it, though less seriously. Estimated values of k , are based respectively on enolization of the substrate catalysed by (CF,),CHO- and of acetophenone catalysed by hydroxide; they are extrapolated to the correct pX using B = 0.8

G INTRAMOLECULAR GENERAL BASE CATALYSIS BY NITROGEN

G. 1

Catalysis of esfer hydrolysis

,/&

Ester N(HO)E--4ln

Ref.

PK,

kb.

T

EM Accuracy

No observed catalysis.’

C0,Ph H

N(HO)E-qx

G. 1 . 1 G.1.2

I

Me,N(CH,),CO,Ph Me,N(CH,),C0,C6H,N0,-p

G.1.3

bpc

bsc

CO,C,H,NO,-p

8.87 2.75 x lo-’ 8.86 3.23 x lo-,

20.6 >20 20.6 >0.5

y

4.01 8.82 x lo-‘

39.6

0.25

y

y

o N M e 2 G. 1.4

e*f

4.26

4.4 x

30

13

p

-

2.5 x lo-’

30

2

p

6.1

8.5 x

50

70

p

y

C0,Ph

G. 1.5

p-nitrophenyl ester of G.1.4

e

N(HO)E-qx

G.1.6

9ii HN N(HO)[email protected]

G.1.7

Cp

CH,COO N(H0)E- 7411

G.1.8

/

qi N

H

h

‘*’

3.09

4.37 x 10-4

55

Y

6.50

1.67 x

50

0.38

Ester

G.1.9

f

Ref.

QK,

k,,,

T

EM Accuracy

1.1

6.90 4.33 x

50

0.63

p

‘-1

4.57 2.67 x

50

4.9

/3

‘-1

4.85

5.17 x

50

7.0

p

‘*I

5.62 4.83 x

50

2.8

p

OAc

G.l.10 iOAC

G.l.ll (OAC

H G.1.12

H a*‘*k

5.6

3.5 x lo-’

30

18

p

‘*’

6.8

6.4 x lo-’

60

1.7

p

H N(HO)E--~)II

G.1.14

H

268

ANTHONY J K I R B Y

Ester

Ref.

G.1.15

PK,

kobs

T

EM Accuracy

6.8

1.8 x 10-7

60

0.3

B

6.25

2.3 x

25

1.0

/3

N(H0)E-1 l4n

G.1.16

ZNH

0

CONH,

Felton and Bruice, 1969 Kirby and Lloyd, 1976 The reference intermolecular reaction is between trimethylamine and the corresponding aryl acetate at 20° (Bruice and Benkovic, 1963). This gives an upper limit for k, because the mechanism is nucleophilic The reference intermolecular reaction is between trimethylamine and p-nitrophenyl quinoline-6carboxylate (Bruice and Bruice, 1974). It is not corrected for basicity because the Me,N group must be rotated out of plane in the transition state for the intramolecular reaction. (Datum in 20% ethanol) In 20% acetonitrile (Bruice and Bruice, 1974). The reference intermolecular reaction is with quinuclidine and is corrected for pK, using /3 = 0.47 'Rate constant estimated from a Hammett plot for a series of substituted compounds @ = 0.97) #Fife et al., 1978. Compare G.1.7 for the calculation of EM on the same scale. The correction used for conversion to benzoyl is the same as for cinnamoyl since k,, is almost the same for this ester and for G. 1.14 Felton and Bruice, 1969. pK, (3.64 at 30°) is the same as that of aspirin. A direct rate comparison would give EM = 116 M (based on 13 M for aspirin), but G.1.7 reacts with hydroxide some 5 times faster than does aspirin, and intramolecular general base catalysis is more sensitive to the leaving group [p,, = 0.55 for HO- attack on aryl acetates (Bruice ef al., 1962) compared with 0.96 for the intramolecular general base catalysed hydrolysis of substituted aspirins (Fersht and Kirby, 1967a)l. Taking these factors into account, the intrinsic reactivity of G. 1.7 is estimated to be 13 times greater than that of aspirin The reference intermolecular reaction is general base catalysis by imidazole of the hydrolysis of N,O-diacetylserinamide at 100° (Anderson et al., 1961). The second order rate constant for this reaction (1.83 x lo-' dm' mol-' s-' at looo) is compared with the rate constant for the

269

EFFECTIVE MOLARlTlES

intramolecular reaction of compound G.1.8 extrapolated to 100' using the enthalpy of activation measured by the authors and corrected for the different pK, of imidazole (7.05) using /3 = 0.47 and for the poorer leaving group (pK estimated as 15.6, compared with 13.6 of N-acetylserinamide) using p= 0.27. This comparison gives an EM for G.1.8, and those for other compounds in this series were calculated by comparing the rate constants given, after correction for the pK, of the imidazole using p = 0.47. The cinnamoyl (and benzoyl) esters-see note gwere placed on the same scale by allowing a factor of 2.23 for the lower reactivity of the ester of the unsaturated acid (this is the ratio of the second order rate constants for the alkaline hydrolysis of 0-acetyl and 0-cinnamoyl-N-acetylserinamide[data of Anderson ef al. (196 1) and Bender ef al. (1962), respectively] 'Utakaef al., 1976,1977 EM based on aspirin (EM 13 M) by comparison of rates which had been corrected for the higher pK of the general base using p= 0.52 (Fersht and Kirby, 1967b) I Komiyama ef ab, 1977 Boudreau ef al., 1978; Z = PhCH,OCO

G.2 Intramolecular general base catalysis of enolizafion Aminoketone

G.2.1. Me,N(CH,),COCH3 G.2.2 Et,N(CH,),COCHj

Ref.

(I

PK,

k0b*

T

EM Accuracy

9.0 1.32 x lo-) 10.14 3.35 x lo-,

30 25

0.05 0.45

p a

10.01 7.80 x lo-'

25

0.10

a

N-H-4n

G.2.3 Et,N(CH,),COCHj

Coward and Bruice, 1969. The reference intramolecular reaction is the enolization of acetone catalysed by trimethylamine Bell and Timid, 1973. The reference intramolecular reaction is the enolization of the substrate conjugate acid catalysed by ethanolamine (pK, 9.50), and EM is corrected for the different pK, using /?= 0.8 and for the effect of the protonated nitrogen

270

ANTHONY J K I R B Y

G.3 Intramolecular general base catalysis of aminolysis by the amino-group Reaction

Ref.

N-HN(E)-+

R'-C

EM" Accuracy

/!

/ \OR .PH\ HzNUNH G.3.1 G.3.2 G.3.3

+

NH,CH,CH,NH, acetyl imidazole methyl formate phenyl acetate

b C

d. e

a

0.55 0.5 -1

P P

0.94 0.6 -1 1

B P P

0.20 -1

P

0.25 1

P

-1

P

N-HN(E)--Sf G.3.4 G.3.5 G.3.6

NHz(CHz)Wz + acetyl imidazole methyl formate phenyl acetate

G.3.7

p-nitrophenyl acetate

b C

d .e e

a

N-HN(E)-q G.3.8 G.3.9

NH,(CH,),NH, acetyl imidazole phenyl acetate

+

b

d.e

a

N-HN(E)-74

NHz(CH2)JHz + G.3.10 acetyl imidazole G.3.11 phenyl acetate

b

d ,e

a

N-HN(E)-q G.3.12 NHz(CH,)6NH, phenyl acetate

+

d. e

~

EM'S calculated by comparing the second order rate constant for aminolysis by the diamine with the third order rate constant for aminolysis by a monoamine of the same pK, Page and Jencks, 1972 Blackburn and Jencks, 1968 Bruice and Willis, 1965 Gilchrist and Jencks, 1966 a

EFFECTIVE MOLAR I TI E S

27 1

111 INTRAMOLECULAR GENERAL ACID CATALYSIS

H. 1

Intramolecular general acid catalysis by the carboxyl group

Compound

Ref.

PK,

kobs

T

EM

Accuracy

4.09

1.24 x lo-*

25

(0.2

Y

6.7 x lo-)

15.5

>I

Y

3 x 10-3

15.5

20

P

4.49 x 10-3

25

3.5

a

1.83 x lo-,

10

2.2

a

CO,H-O=C-Sfx H.l.l

& H,O:

H

0

COZH-N(CO)-Sfx H. 1.2

COzH-O(CO)-Sfx H.1.3

c.d

0

7

0

~

-

0

$22 0

H.1.4

;o;4 HO HO

4.3

9 H HO

03

H.1.5

0 ’

/

0-P- 0 HOH&>P 0-

-

2 72

ANTHONY J K I R B Y

Compound

H.1.6

qi?

Ref.

PK,

k,,,

T

EM

Accuracy

*

5.72 4.72

2.71 x lo-, 0.89

15 39

6500 4600

P P

I

3.77 4.11 3.83 3.63 3.33

1.04 x 1.00 x 7.6 x 8.9 x 2.46 x

10, 10, lo3 lo' lo4

25 25 25 25 25

1

3.77

2.05 x lo3

25

9500

P

3.68

4.38 x

65


Y

5.56

6.31 x

30

38

a

0

phYoEt

H.1.7 H.1.8 H.1.9 H.l.10 H.l.ll

X=Y=H

'

X = Me, Y = H X = H, Y = Me

X = H, Y = OMe X = H.Y = CI

H.1.12

'

2.9 x 2.7 x 2.5 x 1.9 x 1.8 x

lo4 lo4 lo4 lo4 lo4

p p p p p

C02H(0)CO--6fx H.1.14

CI

EFFECTIVE M O L A R I T I E S

273

Bell and Page, 1973. Reference intermolecular reaction is the acetic acid catalysed enolization of the corresponding methyl ester. The EM is not corrected for the pK, difference (correction would reduce EM) because there is some uncertainty about the mechanism in this comparison *Kirby et al., 1974. The external general acid catalysed reaction becomes independent of catalyst concentration at about 1 M as is the intramolecular reaction This rate constant contains the equilibrium constant for the formation of the tetrahedral intermediate shown Kirby and Rao (unpublished). The reference reaction is the H,O+-catalysed hydrolysis of the methyl ester (Aldersley el al., 1974a) corrected for the pK, of the neighbouring group (taken as that of pmethoxypropionic acid) using /3 = 0.5 CCapon and Walker, 1971. The reference intermolecular reaction is the mutarotation of Dglucose, catalysed by a carboxylic acid of pK, 4.3 'Bailey el al., 1970. The reference intermolecular reaction is the phosphate-catalysed mutarotation of D-glucose under the same conditions 8 Data in 50% dioxan-water (Fife and Anderson, 1971). The reference intermolecular reaction is the hydrolysis of 2-phenoxytetrahydropyranat 50° catalysed by formic acid (pK,4.64 under these conditions). The EM given by the authors (580 M) is a lower limit because no corrections were made for T or pK,. Applying both corrections (a= 0.5, AH$ = 10-15 kcal mol-I) gives EM 4-9 x 103 * In 3096 dioxan (Glenn and Kirby, unpublished). The reference intermolecular reaction is the hydrolysis of the methyl ester catalysed by a general acid (RC0,H) of pK, 4.72 Buffet and Lamaty, 1976. The pK,-values quoted are for the Corresponding methoxymethoxybenzoic acids. The reference intramolecular reaction is the acetic acid catalysed hydrolysis of the methyl ester in each case corrected for differences in pK, using a= 0.5 (Capon and Nimmo, 1975) 'Fife and Anderson, 1971. The reference intermolecular reaction is the hydrolysis of the methyl ester catalysed by formic acid (pK, of the substrate assumed the same as for H1.7) kCapon and Page, 1972b. Reference reaction is the acetic acid catalysed hydrolysis of the substrate corrected for the pK, difference using a= 1 (Capon and Page, 1972a) 'In 50% dioxan (Fife and Przystas, 1977). The reference intermolecular reaction is the hydrolysis of the acetal group of the corresponding methyl ester by a carboxylic acid of pK, 5.56. The value of k, was calculated from the buffer catalysis data given for three carboxylic acids using buffer pK,'s measured in 50% dioxan (at SO0) by Fife and Brod (1970) a

'

H.2

Intramolecular general acid catalysis by the hydroxyl group Compound

H.2.1

PhNHNH9I

Ref.

a

PK,

10.4

k0bl

T

EM Accuracy

1.83 x lo-'

25

0.1

y

ANTHONY J. K I R B Y

274

Compound

Ref.

PK,

kobs

T

EM Accuracy

Data of Alves e f a/. (1978), in 20% ethanol. The intermolecular reference reaction is the general acid catalysed addition of phenylhydrazine to the methyl ether, calculated from kH,O+ using a = 0.35 and determined for the reaction with o-methoxybenzaldehyde (Bastos and do Amaral, 1979). The EM, which is in some doubt because of possible mechanistic complications, is determined by comparison of the rate constant given (dm3 mol-I s-I) with the third order rate constant for the reference reaction Capon and Walker, 1974. The reference intermolecular reaction is the phenoxide-catalysed mutarotation of the 6-O-phenoxy-compound, corrected for pK,

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EFFECTIVE M 0 LAR I T I ES

275

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98,4275

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101,6981

Grob, C. A. (1969).Angew. Chem. Internut. Edn. 8,535 Grob, C. A. and Jenny, F. A. (1960). Tet. Lett. 25

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